epidermal-growth-factor and Psoriasis

The 3 major features of psoriasis--abnormal differentiation of keratinocytes, hyperproliferation of keratinocytes, and infiltration of inflammatory components into the skin--can be quantified by measuring levels of certain biochemical markers. Psoriasis is associated with upregulation or downregulation of several of these markers. Tazarotene helps to normalize the levels of the markers, thereby bringing about clinical improvement.

Topics: Administration, Cutaneous; Biomarkers; Epidermal Growth Factor; Humans; Keratinocytes; Keratolytic Agents; Nicotinic Acids; Psoriasis

Transforming growth factor alpha (TGF alpha) is a close relative of epidermal growth factor (EGF), the first polypeptide mitogen discovered in 1962 (Cohen, 1962). TGF alpha, like EGF, exerts its effect on cells through binding to the EGF-Receptor (EGF-R). Here we review the molecular and cell biology of TGF alpha before proceeding to describe our own work on signaling molecules induced in response to activation of the EGF-R.

Topics: Amino Acid Sequence; Animals; Cell Transformation, Neoplastic; Epidermal Growth Factor; ErbB Receptors; Humans; Models, Biological; Molecular Sequence Data; Protein Structure, Secondary; Psoriasis; ras Proteins; Signal Transduction; Transforming Growth Factor alpha

Reconstruction of a living skin equivalent provides an in vitro model for the study of skin biology and pharmacology in a tissue organization whose cells differentiate similarly to skin cells in the body. This simplified skin equivalent, composed of normal or abnormal cells, is obtained in two steps: formation of a dermal equivalent is achieved first and this dermis is then covered with an epidermal equivalent. Each of these tissues, as well as the interactions between them, can then be studied. Using this model, we have demonstrated that normal fibroblasts promote epidermal growth, that psoriatic fibroblasts induce increased proliferation of normal keratinocytes, and that the effects of pharmacological agents (such as retinoids) on keratinocyte growth are modulated by fibroblasts.

Topics: Cell Communication; Collagen; Culture Media; Epidermal Growth Factor; Epidermis; Extracellular Matrix; Fibroblasts; Humans; In Vitro Techniques; Keratinocytes; Lipopolysaccharides; Psoriasis; Retinoids; Skin; Skin Physiological Phenomena; Stimulation, Chemical

Cell growth is controlled by two types of genes, i.e., activating genes (oncogenes) and negative regulator genes (antioncogenes). Studies have shown that malignant transformation of a cell can result from either increased oncogene activity or decreased antioncogene activity. Current knowledge of genes relevant to dermatology is discussed.

Topics: Animals; Cell Transformation, Neoplastic; Epidermal Growth Factor; Genes, p53; Genes, Tumor Suppressor; Humans; Mice; Proto-Oncogenes; Psoriasis; Skin Neoplasms

Topics: Epidermal Growth Factor; Humans; Keratinocytes; Psoriasis; Skin; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factors

Topics: Animals; Arachidonic Acids; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Epidermal Growth Factor; Phospholipids; Psoriasis; Skin; Swine

Topics: Animals; Cell Cycle; Cell Division; Cell Survival; Cells, Cultured; Culture Techniques; DNA; Epidermal Cells; Epidermal Growth Factor; Epidermis; Growth Inhibitors; Guinea Pigs; Homeostasis; Mice; Models, Biological; Nucleotides, Cyclic; Psoriasis; Tissue Extracts; Trypsin

The present study observed the clinical effect of modified Yiyi Baijiang Decoction on psoriasis vulgaris and explored its influence on growth factors and inflammatory factors in the serum and skin tissues. A total of 130 patients were randomly divided into control group and experimental group, with 65 cases in each group. The patients in the control group received Acitretin Capsules and Calcipotriol Ointment, and those in the experimental group received modified Yiyi Baijiang Decoction combined with external application for four weeks. The psoriasis area and severity index(PASI), blood vessel count in the superficial dermis(SDBVC), skin thickness(STK), and traditional Chinese medicine(TCM) symptoms were observed before and after treatment. The growth factors [epidermal growth factor(EGF), endothelial cell-specific molecule-1(ESM-1), fibroblast growth factor-23(FGF-23), and transforming growth factor-β1(TGF-β1)] and inflammatory factors [nuclear factor-κB(NF-κB), prealbumin(PA), CC chemokine ligand 20(CCL20), and procalcitonin(PCT)] in the serum and skin tissues were detected. The total effective rate was 98.5% in the experimental group, higher than that 83.1% in the control group(P<0.05). Compared with the control group after treatment, the experimental group showed decreased PASI, SDBVC, STK, TCM symptoms, ESM-1, FGF-23, TGF-β1, NF-κB, CCL20, and PCT(P<0.05), and increased EGF and PA(P<0.05). The incidence of adverse events was 1.5% in the experimental group, lower than that 21.5% in the control group(P<0.05). The results showed that modified Yiyi Baijiang Decoction could effectively relieve skin lesions in patients with psoriasis vulgaris and improve the growth factors and inflammatory factors in the serum and skin lesions, with high safety.

Topics: Epidermal Growth Factor; Hot Temperature; Humans; NF-kappa B; Psoriasis; Transforming Growth Factor beta1

To investigate the impact of serum epidermal growth factor (EGF) on progressive psoriasis vulgaris and the regulatory effect of Chinese herbal medicine on it.. Serum level of EGF was measured in 31 patients with progressive psoriasis vulgaris (the tested group) and 17 healthy subjects (the control group) by ELISA. The changes in EGF level and condition of illness were observed before and after patients orally administered Chinese composite recipe for clearing heat, cooling blood and removing toxic substances for 10 weeks, and the severity of illness was assessed by psoriasis area and severity index (PASI) as well.. Serum level of EGF in patients was 175.35 +/- 179.86 ng/L before treatment, markedly higher than that in healthy subjects (72.05 +/- 63.01 ng/L), showing significant difference between them (t = - 2.888, P = 0.006); it reduced to 121.67 +/- 94.74 ng/L after treatment, significantly different to that before treatment (t = 2.155, P = 0.04), but still higher than that in the control (t = - 2.146, P = 0.037). Average PASI was 9.65 +/- 5.82 before treatment and 5.74 +/- 4.69 after treatment, displaying a significant reduction (t = 7.740, P < 0.01). Linear regression analysis showed no apparent correlation between serum EGF level and PASI (r = 0.030, P = 0.872; r = 0.050, P = 0.793).. Serum level of EGF might be an important factor related to the progress of psoriasis. Chinese herbal medicine for clearing heat, cooling blood and removing toxic substances can lessen the severity of psoriasis, its action in reducing serum EGF is possibly one of the mechanisms for these kinds of herbs in treating psoriasis.

Topics: Adolescent; Adult; Aged; Drugs, Chinese Herbal; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Psoriasis; Young Adult

Calcitriol and calcipotriol are widely used in the topical treatment of psoriasis. However, studies comparing both treatment modalities are scarce. Especially, there are almost no studies comparing the effects on epidermal cell populations in a quantitative manner.. The aim of this study was to quantitatively compare the effects of topical calcitriol and topical calcipotriol on clinical scores and epidermal subpopulations.. From five patients with stable plaque psoriasis, skin biopsies were taken from two symmetrical regions on the trunk or extremities before and after treatment with either calcitriol or calcipotriol. Frozen sections were labelled immunofluorescently using direct immunofluorescence for beta-1 integrin and the Zenon labelling technique for keratin (K) 6, K10 and K15. The digital photographs of the stained sections were quantitatively analysed and the results of both treatments were compared.. The clinical SUM-score improved significantly for both the calcitriol- and the calcipotriol-treated lesions. In the calcipotriol-treated group the expression of K10 and K15 increased and the expression of K6 decreased significantly. No changes were seen for the marker beta-1 integrin. In the calcitriol-treated group none of the markers changed significantly. A tendency towards significance was seen for the changes in the expression of K6 and K15 in favour of calcipotriol.. Both calcitriol and calcipotriol gave a significant improvement in clinical scores. However, treatment with calcipotriol resulted in a normalization of K6, K10 and K15, whereas treatment with calcitriol did not. Comparison of both treatments showed a tendency towards significance for the above-mentioned markers for calcipotriol only.

Topics: Administration, Topical; Calcitriol; Calcium Channel Agonists; Cell Differentiation; Cell Proliferation; Dermatologic Agents; Double-Blind Method; Epidermal Growth Factor; Humans; Immunohistochemistry; Keratins; Ointments; Psoriasis; Treatment Outcome

Epidermal growth factor (EGF) is a mitogen that stimulates cell division of various cells of epidermal origin. The present study was undertaken to clarify whether the serum level of EGF is correlated with the disease activity during local therapy with dithranol in psoriasis. We examined serum EGF concentrations in acute and chronic psoriasis before and after topical treatment with dithranol and the correlation with Psoriasis Activity and Severity Index (PASI). Male patients were divided into two groups: acute psoriasis (AP, 18 cases) and chronic psoriasis (CP, 17 cases). A control group C consisted of 20 healthy male volunteers. Radioimmunoassay of EGF was performed using the reagent pack (Amersham, UK). In the CP group mean EGF was higher before treatment than in the AP and C groups, but not significantly. EGF concentration after local treatment was higher in the CP group than the AP group (P < 0.02); the AP group, however, showed statistically significant decrease of EGF after the treatment (P < 0.04). No correlation between EGF and PASI was found. Serum EGF concentration increased in 19/35 treated patients.

Topics: Acute Disease; Administration, Cutaneous; Administration, Topical; Anthralin; Anti-Inflammatory Agents; Chronic Disease; Epidermal Growth Factor; Humans; Male; Psoriasis; Severity of Illness Index; Treatment Outcome

Topics: Acute Disease; Adult; Biomarkers; Chronic Disease; Epidermal Growth Factor; Humans; Male; Prognosis; Psoriasis; Reference Values; Severity of Illness Index

Psoriasis is characterized by increased dermal vascularity, indicating that aberrant angiogenesis is associated with the pathogenesis of psoriasis. Data on angiogenesis-related factors in psoriasis patients are limited. We explored serum levels of angiogenesis-related factors in patients with psoriasis, and investigated their association with clinical severity and laboratory data. Psoriasis patients visiting our hospital from April 2013 to April 2018 and healthy controls were included in this study. Serum levels of angiopoietin-1, fibroblast growth factor (FGF)-basic, epidermal growth factor (EGF), platelet endothelial cell adhesion molecule (PECAM)-1, placental growth factor, and vascular endothelial growth factor (VEGF) were measured by LEGENDplex. Serum samples obtained from 10 healthy controls, 18 patients with psoriasis vulgaris (PsV), 24 patients with psoriatic arthritis (PsA), and 13 patients with generalized pustular psoriasis (GPP) were analyzed. The serum angiopoietin-1 level was elevated in the PsV, PsA, and GPP patients. GPP patients had a higher serum VEGF level than healthy controls. In contrast, serum levels of EGF and PECAM-1 were lower in the PsV, PsA, and GPP patients than in healthy controls. The serum FGF-basic level was lower in the PsA and GPP patients than in healthy controls. Serum levels of FGF-basic in PsA and GPP patients, PECAM-1 in PsA patients, and VEGF in GPP patients became closer to the respective levels in healthy controls after systemic therapy. The serum FGF-basic level was positively correlated with the psoriasis area and severity index and the number of circulating eosinophils in GPP patients. The serum VEGF level was correlated positively with the serum C-reactive protein (CRP) level and erythrocyte sedimentation rate, and negatively with the serum albumin level in GPP patients. In conclusion, our exploratory study revealed that psoriasis affects serum levels of certain angiogenesis-related factors. Some of these factors could be biomarkers of treatment outcomes, clinical severity, and systemic inflammation.

Topics: Angiopoietin-1; Arthritis, Psoriatic; Epidermal Growth Factor; Female; Humans; Placenta Growth Factor; Platelet Endothelial Cell Adhesion Molecule-1; Psoriasis; Vascular Endothelial Growth Factor A

Psoriasis is a chronic inflammatory skin disease in which growth activity is more prominent than inflammatory activity at the centre of lesional skin (CE skin). This growth activity is partly influenced by growth factors (GFs) that play an important role in cell growth and inflammation during the plaque development. In this study, we identified potential GFs in CE skin and predicted their regulatory functions and biological activity in mediating transcripts in the plaques. Samples of uninvolved skin (UN skin) and CE skin were biopsied from patients with psoriasis vulgaris for RNA-sequencing analysis in order to identify differentially expressed genes (DEGs). Our finding revealed that epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF) signalling were enriched by CE/UN skin-derived DEGs. Additionally, several EGFR ligands, namely EGF, heparin-binding EGF like growth factor (HB-EGF), amphiregulin (AREG) and transforming growth factor (TGF)-α, as well as TGF-β1, TGF-β2, vascular endothelial growth factor-A, FGFs, PDGF-B and HGF, were predicted to be GF regulators. The regulatory pattern and biological activity of these GF regulators on mediating the CE/UN skin-derived DEGs was demonstrated. This study provides a novel hypothesis regarding the overall regulatory function of GFs, which appear to modulate the expression of the transcripts involved in inflammation and growth in the CE skin. In addition, some GFs may exert anti-inflammatory effects. Further investigations on the mechanisms underlying this regulation may contribute to a deeper understanding of psoriasis and the identification of potential therapeutic targets for patients with psoriasis.

Topics: Epidermal Growth Factor; Fibroblast Growth Factors; Humans; Inflammation; Psoriasis; Skin; Vascular Endothelial Growth Factor A

Thioredoxin-interacting protein (TXNIP), also known as Vitamin-D upregulated protein-1 (VDUP-1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25-dihydroxyvitamin D

Topics: Carrier Proteins; Epidermal Growth Factor; ErbB Receptors; Humans; Keratinocytes; Psoriasis; Thioredoxins; Transforming Growth Factor alpha

One of the earliest events in the development of psoriatic lesion is a vascular network expansion. The abnormal vascular network is associated with increased endothelial cells (ECs) survival, proliferation, adhesion, migration, angiogenesis and permeability in psoriatic lesion. Our previous study demonstrated that epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) derived from psoriatic dermal mesenchymal stem cells (DMSCs) promoted cell-cell adhesion, migration and angiogenesis of ECs, but the molecular mechanism of upstream or downstream has not been explored. So, this study aimed to explore the association between EDIL3 derived from DMSCs (DMSCs-derived EDIL3) and psoriasis-associated angiogenesis. We injected recombinant EDIL3 protein to mouse model of psoriasis to confirm the roles of EDIL3 in psoriasis. Besides, we employed both short-interference RNA (si-RNA) and lentiviral vectors to explore the molecular mechanism of EDIL3 promoting angiogenesis in psoriasis. In vivo, this research found that after injected recombination EDIL3 protein, the epidermis thickness and microvessel density were both elevated. EDIL3 accelerated the process of psoriasis in the IMQ-induced psoriasis-like mouse model. Additionally, we confirmed that in vitro DMSCs-derived EDIL3 is involved in the tube formation of ECs via αvβ3-FAK/MEK/ERK signal pathway. This suggested that DMSCs-derived EDIL3 and αvβ3-FAK/MEK/ERK signal pathway in ECs play an important role in the pathogenesis of psoriasis. And the modification of DMSCs, EDIL3 and αvβ3-FAK/MEK/ERK signal pathway will provide a valuable therapeutic target to control the angiogenesis in psoriasis.

Topics: Animals; Calcium-Binding Proteins; Cell Adhesion Molecules; Cell Proliferation; Discoidins; Endothelial Cells; Epidermal Growth Factor; Mice; Mitogen-Activated Protein Kinase Kinases; Neovascularization, Pathologic; Psoriasis; RNA

IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.

Topics: Biopsy; Cell Proliferation; Cytokines; Dendritic Cells; Epidermal Growth Factor; Epidermis; Gene Expression Regulation; Humans; Interleukin-1; Interleukin-17; Interleukin-23 Subunit p19; Keratinocytes; Monocytes; Psoriasis; Signal Transduction; Skin; Th17 Cells; THP-1 Cells; Tumor Necrosis Factor-alpha

Pathogenesis of psoriasis involves epidermal growth factor (EGF) that participates in keratinocyte proliferation, angiogenesis and cell differentiation through binding to soluble epidermal growth factor receptor (sEGFR). It is synthesised by, among others, keratinocytes, especially within psoriatic skin.. To evaluate EGF and sEGFR plasma concentrations during topical psoriatic treatment.. Blood samples were collected from 51 patients with plaque psoriasis. EGF and sEGFR plasma concentrations were examined with immunoenzymatic method prior and 14 days after topical treatment. The outcomes were analyzed with respect to PASI.. Mean EGF concentration was higher in the plasma of psoriatic patients compared to the control group (p = .401) while mean sEGFR concentration was over twofold lower compared to the control group (p < .001). After the therapy, an insignificant decrease in EGF plasma concentration (p = .835) and a significant increase in sEGFR concentration (p = .017) compared to initial values were observed. The coefficient of EGF/sEGFR concentration calculated for each individual had similar values before and after the treatment (p = .009), both of which were significantly higher compared to control group (respectively p < .001, p < .008).. Epidermal growth factor and its soluble receptor may be a useful markers in monitoring clinical course of psoriasis and the effectiveness of therapy.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Case-Control Studies; Dermatologic Agents; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Immunoassay; Male; Middle Aged; Psoriasis; Severity of Illness Index; Young Adult

VEGF and EGF are assumed to be involved in the pathogenesis of psoriasis, while the impacts of their polymorphisms on psoriasis are inconsistent. Therefore, we hope to clarify these relationships in the Chinese Han population.. A total of 131 patients with psoriasis vulgaris and 176 controls were enrolled. The polymorphisms rs833061 (T > C), rs10434 (G > A) in VEGFA, and rs4444903 (G > A), rs2237051 (A > G) in EGF of each participant were detected. The patients were treated with calcipotriol plus acitretin 30 mg/day for 8 weeks.. No SNPs of rs833061, rs10434, rs4444903 and rs2237051 were found to be associated with psoriasis susceptibility and efficacy. Although the mutation of rs10434A was associated with baseline disease severity (p = 0.026), and rs2237051G allele was associated with increased erythema during treatment (p = 0.015).. The allele of rs2237051 G increased the erythema during the treatment, and no polymorphism of VEGF and EGF gene was found to be associated with the susceptibility and efficacy in psoriasis.

Topics: Acitretin; Adult; Calcitriol; China; Drug Administration Schedule; Epidermal Growth Factor; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Psoriasis; Vascular Endothelial Growth Factor A

Psoriasis is a T-cell-mediated skin disease with autoimmune nature that is generally not observed in animals, this lack of a relevant experimental animal model of psoriasis has hindered the investigation of pathogenesis of disease. Application and systemic delivery of small interfering RNAs offer many effective therapeutic advantages for gene regulation in the skin. In this study, we present an IMQ animal model of psoriasis and designed a safe fusion peptide carrier, spherical nucleic acid gold nanoparticles conjugate, to improve penetration of the siRNA into the cells and skin and their targeting ability to gene regulation. We evaluated the model of psoriasis and EGFR siRNA treatment (as spherical nucleic acid nanoparticles), phenotypically (signs of erythema, scaling, inflammation and thickening), microscopic evaluation of cell proliferation and immunohistochemically evaluation of CD3, CD4, and CD8 markers. Also, we monitored suppression of EGF&EGFR genes after treatment of A431 cells by SNA-NCs. The expression of genes was validated by qRT-PCR in human skin cells. The results showed that the SNA-NCs were stable and non-toxic. In vitro experiments indicated that EGF&EGFR siRNAs conjugated with spherical nucleic acid gold nanoparticles can significantly reduce gene expression in cells. In vivo experiments showed that the topical application of siRNAs delivered by SNA-NCs through the skin can significantly inhibit the proliferation of cells. Microscopic evaluation of mice back skin and immunohistochemistry process approved Inhibitory effect of SNA-NCs siRNA in the mouse model of psoriasis. Since the proliferation of T cells was crucial for the development of a psoriatic phenotype. These results demonstrate that topical application of SNA-NCs siRNA may improve psoriatic-like skin lesions by suppressing gene expression and functional activity of T cell production.

Topics: Animals; Cell Line, Tumor; Cell Survival; Epidermal Growth Factor; Gene Expression Regulation; Genes, erbB-1; Gold; Humans; Male; Metal Nanoparticles; Mice, Inbred BALB C; Psoriasis; RNA, Small Interfering

IFI27 is highly expressed in psoriatic lesions but its function has not been known. The present study aimed to explore its role in proliferation of epidermal keratinocytes.. IFI27 knockdown and over-expression in keratinocytes were used to compare their proliferation, by MTT assay, apoptosis (by annexin V binding) and cell cycle progression by flow cytometry. Formation of cyclin A/CDK1 complex was examined by a co-immunoprecipitaion method. Anti-proliferation effects of IFI27 were also examined in vivo by topical application of IFI27 siRNA on imiquimod-induced psoriatic lesions, in a mouse model.. Epidermal growth factor was demonstrated to increase IFI27 expression by prolonging half-life of IFI27 protein. The IFI27 knockdown in keratinocytes reduced the proliferation rate, but had no effect on apoptosis nor on apoptosis-related genes. Interestingly, IFI27 knockdown resulted in S-phase arrest that was found to be associated with increased Tyr15 phosphorylation of CDK1, reduced CDC25B and reduced formation of cyclin A/CDK1 complex. In addition, IFI27 knockdown was also shown to activate p53 by Ser15 phosphorylation and increase p21 expression. Topical application of IFI27 siRNA on imiquimod-induced psoriatic lesion in a mouse model reduced epidermal thickness, formation of rete ridges and PCNA expression.. Our study demonstrates for the first time, that cell function of IFI27 is involved in proliferation of skin keratinocytes both in vitro and in vivo. It suggests that IFI27 might be a suitable target for development of a novel anti-psoriasis therapy.

Topics: Aminoquinolines; Animals; Apoptosis; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Proliferation; Cells, Cultured; Cyclin A; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Enzyme Activation; Epidermal Growth Factor; Humans; Imiquimod; Keratinocytes; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Phosphorylation; Psoriasis; RNA Interference; RNA, Small Interfering; S Phase Cell Cycle Checkpoints; Skin; Tumor Suppressor Protein p53

Epidermal growth factor receptors (EGFRs) are overexpressed in psoriatic keratinocytes, and regulate cell growth, proliferation and differentiation through binding to epidermal growth factor (EGF). The role of EGF and EGFRs in the pathogenesis of psoriasis and the contribution of their measurement to psoriasis management are still unknown.. To evaluate serum concentrations of EGF, soluble (s)EGFRs and EGF content in psoriatic scales of patients with severe psoriasis, and to analyse their association with the clinical activity of the disease.. Serum samples and plaque scales were collected from 51 patients with plaque-type psoriasis. Concentrations of EGF and sEGFR in serum and of EGF in scales were measured using enzyme immunoassay. Data were analysed with respect to baseline Psoriasis Area and Severity Index (PASI).. Mean serum EGF concentration in patients was higher than in controls (701 ± 72 vs. 586 ± 63 pg/mL), but the difference was not significant. Mean serum concentration of sEGFR was significantly lower than controls (40.8 ± 1.4 vs. 86.4 ± 11.3 ng/mL, P < 0.001). Serum levels of EGF showed a significant positive correlation and EGFR showed a significant negative correlation with PASI (P < 0.05). No correlation was seen between PASI and EGF content in scales or between EGF and sEGFR levels. Serum EGF concentrations reached the highest mean level (914 ± 138 pg/mL) in patients with PASI > 20, and this was significantly higher than the mean of 414 ± 82 pg/mL in the group with PASI < 10. Mean sEGFR serum concentrations remained significantly lower than those of controls, irrespective of disease severity.. Compared with controls, patients with psoriasis had increased EGF and decreased sEGFR levels in serum. EGF and sEGFR levels correlated with disease severity.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Male; Middle Aged; Psoriasis; Severity of Illness Index; Young Adult

In patients affected by psoriasis, use of a topical formula containing a derivative of zebrafish embryos was associated with reduced skin inflammation and dermal turnover, as well as a generally better outcome. In an attempt to understand the molecular mechanisms lying beyond these findings, we investigated the anti-proliferative effects of the zebrafish embryos derivative by addressing the mitochondrial function (MTT assay) and cell nuclei distribution (Hoestch staining). In cell cultures stimulated with fetal calf serum (FCS) or epidermal growth factor (EGF), the zebrafish derivative significantly inhibited cell proliferation induced by either approach, although the effect was stronger in cells stimulated with FCS. These results suggest that the zebrafish embryos derivative may dampen increased cell proliferation; this observation may be relevant to cutaneous pathologies related to altered proliferative mechanisms, including psoriasis.

Topics: Animals; Cattle; Cell Nucleus; Cell Survival; Cells, Cultured; Culture Media; Drug Evaluation, Preclinical; Epidermal Growth Factor; Fetal Blood; Humans; In Vitro Techniques; Keratinocytes; Mitochondria; Psoriasis; Tissue Extracts; Zebrafish

EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequent downregulation by ephrin-A1 ligand. The objective of this study was to determine whether the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition in which keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2, and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest upregulation, a finding that was confirmed by quantitative reverse-transcriptase-PCR, immunohistochemistry (IHC), and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiate in high calcium or a three-dimensional (3D) raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1α. These findings suggest that ephrin-A1-mediated downregulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation.

Topics: Biopsy; Case-Control Studies; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cytokines; Ephrin-A1; Epidermal Growth Factor; Epidermis; Humans; Keratinocytes; Psoriasis; Receptor, EphA2; Signal Transduction

Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function.

Topics: Animals; Cell Differentiation; Epidermal Cells; Epidermal Growth Factor; Epidermis; Gene Expression Regulation, Enzymologic; Genomics; Hair Follicle; Hedgehog Proteins; Homeostasis; Keratinocytes; Melanocytes; Mice; Pigmentation; Protein Serine-Threonine Kinases; Psoriasis; Signal Transduction; Transcriptome; Wnt Proteins

Topical indigo naturalis ointment is clinically proved to be an effective therapy for plaque-type psoriasis. Indirubin, as the active component of indigo naturalis, inhibits cell proliferation of epidermal keratinocytes. However, the detailed underlying mechanism is not fully understood.. To further investigate the anti-proliferating effects of indigo naturalis and indirubin on epidermal keratinocytes.. The decreased expression of CDC25B in indigo naturalis- or indirubin-treated epidermal keratinocytes, as revealed by cDNA microarray analysis, was studied. The CDC25B expression was examined under different serum concentrations and compared between primary and immortalized keratinocytes. The activation of EGFR and the effect of EGF on the cell proliferation and CDC25B expression were also investigated in epidermal keratinocytes. RT/real-time PCR and western blot method were used to analyze the CDC25B expression at the mRNA and protein levels, respectively.. Indigo naturalis and indirubin were confirmed to down-regulate CDC25B expression significantly at both the mRNA and protein levels. The growth-dependent expression of CDC25B was demonstrated by the increased expression in serum-stimulated and immortalized keratinocytes. The activation of EGF receptor, known to be highly expressed in psoriatic lesions, was inhibited by indigo naturalis or indirubin. The cell proliferation and CDC25B expression of epidermal keratinocytes were induced by EGF alone and confirmed to be inhibited by indigo naturalis or indirubin.. Except being a common therapeutic target in various cancers, CDC25B also plays an important role in the hyper-proliferation of epidermal keratinocytes which can be suppressed by anti-psoriatic drug indigo naturalis and its component, indirubin.

Topics: cdc25 Phosphatases; Cell Proliferation; DNA, Complementary; Dose-Response Relationship, Drug; Epidermal Cells; Epidermal Growth Factor; Epidermis; ErbB Receptors; Gene Expression Regulation; Humans; Indigo Carmine; Indoles; Keratinocytes; Oligonucleotide Array Sequence Analysis; Plant Extracts; Psoriasis; Skin; Time Factors; Transfection

CCHCR1 (Coiled-Coil α-Helical Rod protein 1), within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene with the psoriasis associated risk allele CCHCR1*WWCC. Although its expression pattern in psoriatic skin differs from healthy skin and its overexpression influences cell proliferation in transgenic mice, its role as a psoriasis effector gene has remained unsettled. The 5'-region of the gene contains a SNP (rs3130453) that controls a 5'-extended open reading frame and thus the translation of alternative isoforms. We have now compared the function of two CCHCR1 isoforms: the novel longer isoform 1 and the previously studied isoform 3. In samples of Finnish and Swedish families, the allele generating only isoform 3 shows association with psoriasis (P<10(-7)). Both isoforms localize at the centrosome, a cell organelle playing a role in cell division. In stably transfected cells the isoform 3 affects cell proliferation and with the CCHCR1*WWCC allele, also apoptosis. Furthermore, cells overexpressing CCHCR1 show isoform- and haplotype-specific influences in the cell size and shape and alterations in the organization and expression of the cytoskeletal proteins actin, vimentin, and cytokeratins. The isoform 1 with the non-risk allele induces the expression of keratin 17, a hallmark for psoriasis; the silencing of CCHCR1 reduces its expression in HEK293 cells. CCHCR1 also regulates EGF-induced STAT3 activation in an isoform-specific manner: the tyrosine phosphorylation of STAT3 is disturbed in isoform 3-transfected cells. The centrosomal localization of CCHCR1 provides a connection to the abnormal cell proliferation and offers a link to possible cellular pathways altered in psoriasis.

Topics: Alleles; Alternative Splicing; Apoptosis; Cell Line; Cell Proliferation; Centrosome; Cloning, Molecular; Cytoskeleton; Epidermal Growth Factor; ErbB Receptors; Gene Expression; Gene Order; Humans; Intracellular Signaling Peptides and Proteins; Phosphorylation; Polymorphism, Single Nucleotide; Protein Isoforms; Protein Transport; Psoriasis; Signal Transduction; STAT3 Transcription Factor

Psoriasis is a chronic papulosquamous cutaneous disease. The etiology is unknown. Several biochemical and immunological processes, which appear in patients with genetic predisposition, lead to enhanced proliferation of epidermal cells, and inflammation of the dermis. Thyroid gland hormones cause an increase of epidermal growth factor level, which has an important role in keratinocyte proliferation, which may be involved in psoriasis disease.. In this study, we have prospectively examined the function of thyroid gland hormones--TSH, T3, T4, anti-TPO and antithyroglobulin--in 100 psoriatic patients. This database was compared with a control group of 54 patients, without known thyroid gland abnormalities, who were randomly chosen from the endocrinology clinic's medical records.. In the psoriatic patients, an increase in the anti-TPO levels was demonstrated in 9 psoriatic patients (9%), compared to 3 patients in the control group (5.6%). An increase of anti-TG was demonstrated in 3 psoriatic patients (3%) compared to one patient (1.8%) in the control group. An increase of TSH levels was demonstrated in 5 psoriatic patients (5%) compared to 3 patients (5.6%) in the control group. T3 levels were abnormal in 3 psoriatic patients, and T4 levels were abnormal in 2 psoriatic patients, while the T3 and T4 levels in the control group patients were normal.. In our study we didn't observe a statistical difference in the thyroid gland functions between the psoriatic and the control patients. We have observed that in patients with severe psoriasis, there were increased TSH levels and positive auto-antibodies titer compared to patients with mild psoriasis.. The clinical characteristics of the psoriatic patients were connected to the function of the thyroid gland. Nonetheless, the number of patients was low, and more studies are needed to confirm this relationship.

Topics: Adult; Autoantibodies; Cell Proliferation; Comorbidity; Epidermal Growth Factor; Female; Humans; Israel; Keratinocytes; Male; Middle Aged; Prevalence; Psoriasis; Random Allocation; Severity of Illness Index; Skin; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyrotropin

Psoriatic plaques present a complex expression profile, including high levels of cytokines, chemokines and growth factors. Circulating cytokines have been suggested to reflect the activation status of the inflammatory process.. To analyse 20 cytokines, chemokines and growth factors in 14 patients with psoriasis vulgaris at the start and during the course of ultraviolet B treatment.. A multiplex cytokine assay was used.. We identified increased serum levels of epidermal growth factor (EGF) (mean 323 vs. 36·6 pg mL⁻¹, P = 0·0001), interleukin (IL)-1 receptor antagonist (mean 39·1 vs. 14·6 pg mL⁻¹, P = 0·02) and tumour necrosis factor-α (mean 7·5 vs. 4·5 pg mL⁻¹, P = 0·04) at baseline in patients with psoriasis compared with matched controls. None of these cytokines was correlated to the severity of the disease (Psoriasis Area and Severity Index) or decreased with phototherapy, suggesting that sources other than lesional skin contribute to the production of these cytokines. Using cluster analysis, we observed coordinate upregulation of EGF, IL-6, macrophage inflammatory protein-1ß and vascular endothelial growth factor.. The sustained high expression of inflammatory circulating cytokines is a potential mechanism linking psoriasis with its extracutaneous comorbidities.

Topics: Biomarkers; Cytokines; Epidermal Growth Factor; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Psoriasis; Severity of Illness Index; Tumor Necrosis Factor-alpha; Ultraviolet Therapy

The family of human epidermal growth factor receptors (EGFR, HER2-4) exerts key functions in normal and malignant epithelial cells. Both EGFR and HER2 are valuable targets for anti-cancer drugs by interfering with ligand binding, receptor dimerization, or tyrosine kinase activity. A similar therapeutic strategy has been advocated for chronic psoriasis since plaque lesions overexpress EGFR and its ligands. Our aim was to characterize EGFR/HER2 protein expression in skin cultures and to evaluate the effects of tyrosine kinase inhibitors on epidermal outgrowth, morphology, and EGFR activation. Human skin explants were established on cell-free dermis and cultured at the air-liquid interface. The impact of small-molecule HER inhibitors on outgrowth was assayed by fluorescence-based image analysis and histometry. Effects of a dual EGFR/HER2 kinase inhibitor, PKI166, on neoepidermis were studied by immunohistochemistry and Western blot. Receptor immunostaining showed in vivo-like distributions with highest EGFR intensity in the proliferative layers whereas HER2 was mainly expressed by suprabasal keratinocytes. Reepithelialization was associated with EGFR autophosphorylation irrespective of exogenous ligand stimulation. PKI166 inhibited neoepidermal EGFR activation, keratinocyte proliferation, and outgrowth from normal and psoriatic skin explants. The rate of epidermalization in presence of other HER inhibitors varied suggesting that drug specificity, potency, and reversibility determine the dynamic outcome. Overall, agents predominantly targeting EGFR kinase were more efficient inhibitors of epidermal regeneration than an HER2-selective drug. The study illustrates the usefulness of a dynamic skin model and emphasizes the potential of HER-directed approaches to control epidermal growth in hyperproliferative skin disorders.

Topics: Cell Proliferation; Cells, Cultured; Dermis; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epidermal Growth Factor; Epidermis; ErbB Receptors; Humans; Keratinocytes; Models, Biological; Organ Culture Techniques; Protein-Tyrosine Kinases; Psoriasis; Pyrimidines; Pyrroles; Receptor, ErbB-2; Regeneration

Topics: Animals; Epidermal Growth Factor; Epidermis; Epiregulin; Humans; Psoriasis

As a part of synthetic studies on MMP (matrix metalloproteinase)/ADAM (a disintegrin and metalloproteinase) inhibitors, we have preliminarily communicated that azasugar-based compound 1a exhibited a potential inhibitory activity on some metalloprotease-catalyzed proteolytic reactions. To find promising candidates for the topical treatment of psoriasis, we investigated stability in aqueous solution of compound 1a and its derivative 1b and then optimized the P1' substuent (2-5). In the present study, we synthesized novel derivatives of compound 1a and evaluated their inhibitory activity toward MMP-1, -3, and -9, TACE, and HB-EGF shedding, from a viewpoint of versatility of azasugars as a functional scaffold. As a result, it was found that compound 1b demonstrated desirable inhibitory activity as an antipsoriatic agent, and some of the derivatives showed selective inhibitory activity. In addition, it was found that compound 1b exhibited a significant therapeutic effect on a mouse TPA-induced epidermal hyperplasia model. Therefore, compound 1b could become a promising candidate as a practical antipsoriatic agent.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Aza Compounds; Carbohydrates; Disease Models, Animal; Disintegrins; Epidermal Growth Factor; Heparin-binding EGF-like Growth Factor; Hydroxamic Acids; Hyperplasia; Intercellular Signaling Peptides and Proteins; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Models, Molecular; Protease Inhibitors; Psoriasis; Skin; Stereoisomerism; Structure-Activity Relationship; Sulfones

The topological relationships between erbB receptors and ligands of the epidermal growth factor family were characterized by immunocytochemistry in normal and psoriatic epidermis and in proliferating and differentiating human keratinocytes in culture. Spatial colocalization of receptors and ligands was assessed by dual immunostaining. Expression of epidermal growth factor receptor (EGFr), erbB2, and erbB3, but not erbB4, was detected throughout the epidermis, although labeling for erbB2 and erbB3 was accentuated in the upper spinous layers, and EGFr was more strongly labeled in basal cells. Of the tested growth factors, heparin-binding epidermal growth factor (HB-EGF) was diffusely expressed throughout normal and psoriatic epidermis and sparsely colocalized with EGFr in all viable epidermal layers, with increased colocalization in psoriatic epidermis. In contrast, betacellulin and heregulin/neu differentiation factor (NDF) alpha were largely restricted in their distribution to the upper spinous and granular layers. Betacellulin was downregulated in psoriatic keratinocytes. Although heregulin/NDF-beta was undetectable in normal epidermis, it was upregulated in psoriasis. Betacellulin and heregulin/NDF-alpha strikingly colocalized with EGFr and erbB3 receptors in the granular layer and in a declining gradient from the granular zone to the basal layer, respectively. Similar patterns were observed in cultured keratinocytes under proliferative conditions and upon differentiation in high-calcium medium. These morphological data collectively suggest divergent functions for members of the growth factor family, and in particular, we propose that betacellulin and heregulin/NDF-alpha are involved in epidermal morphogenesis and/or in maintenance of the differentiated phenotype.

Topics: Betacellulin; Case-Control Studies; Cell Differentiation; Cell Division; Cells, Cultured; Epidermal Growth Factor; Epidermis; ErbB Receptors; Heparin; Heparin-binding EGF-like Growth Factor; Humans; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Keratinocytes; Neuregulin-1; Psoriasis; Receptor, ErbB-2; Receptor, ErbB-3; Tissue Distribution

Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) has proved to be a mitogen of keratinocytes, which may be involved in the pathogenesis of inflammatory diseases, but its mechanism in psoriasis remains unknown.. To investigate the alteration of HB-EGF in the epidermis of active psoriasis vulgaris.. The expression of HB-EGF in normal skin tissues, uninvolved tissues and psoriatic lesions was detected by in situ hybridization and immunohistochemistry.. HB-EGF mRNA and protein were located in the basal layer of normal epidermis (10/10, 100.00%), with nearly no expression in the suprabasal layers (1/10, 10.00%); the expression of HB-EGF was located not only in the basal layer (21/21, 100.00%), but was also seen as focal overexpression in the suprabasal layers of uninvolved epidermis (20/21, 95.24%) and the marginal part of psoriatic lesions (18/21, 85.71%), while nearly no expression of HB-EGF was found in the central part of psoriatic lesions (1/21, 4.76%).. HB-EGF may play an important role in the early pathogenesis of psoriasis.

Topics: Adolescent; Adult; Base Sequence; Biopsy, Needle; Case-Control Studies; Epidermal Growth Factor; Female; Genetic Markers; Genetic Predisposition to Disease; Heparin-binding EGF-like Growth Factor; Humans; Immunohistochemistry; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Prognosis; Psoriasis; Reference Values; RNA, Messenger; Sensitivity and Specificity; Severity of Illness Index

Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.

Topics: Amphiregulin; Animals; Cell Line; Disease Models, Animal; Drug Stability; EGF Family of Proteins; Epidermal Growth Factor; Glycoproteins; Growth Substances; Heparin-binding EGF-like Growth Factor; Humans; Hydroxylamines; Hyperplasia; Intercellular Signaling Peptides and Proteins; Isoquinolines; Magnetic Resonance Spectroscopy; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Protease Inhibitors; Psoriasis; Recombinant Proteins; Skin; Tetradecanoylphorbol Acetate; Tetrahydroisoquinolines

Epidermal growth factor (EGF) family members and its receptor (EGFR) are thought to have an important role in the proliferation of epidermal keratinocytes. In this report, we investigated the EGF/EGFR system in primary keratinocytes derived from normal and psoriatic lesional skin. EGF elicited the growth of both normal human keratinocytes (NHKs) and psoriatic lesional keratinocytes (PLKs). Interleukin-6 (IL-6) potentiated the EGF-dependent growth of NHKs, but has no observable effect on PLKs, while IL-6 itself showed no growth-stimulating activities in both cell types. Immunodetection and in situ hybridization analyses revealed that IL-6 induces EGFR expression in NHKs in a time- and dose-dependent manner. This EGFR expression decreased reversibly to an undetectable level when IL-6-treated NHKs were re-cultured in IL-6-free conditions. On the other hand, PLKs expressed high levels of EGFR even when unstimulated and the expression level was not affected by IL-6 stimulation. These results suggest that the EGF/EGFR system is involved in the growth of NHKs and PLKs and that IL-6 potentiates NHK growth partly through the induction of EGFR. The different EGFR regulatory system may contribute to the pathogenesis of psoriasis.

Topics: Adult; Cell Division; Epidermal Growth Factor; ErbB Receptors; Gene Expression; Gene Expression Regulation; Humans; Interleukin-6; Keratinocytes; Middle Aged; Psoriasis; Skin

Organ cultures were established from psoriatic lesional skin of 24 different individuals and maintained for 8 days under serum-free, growth-factor-free conditions. Nonlesional skin from 14 of the same individuals and normal skin from another 12 individuals were also maintained in organ culture. At the end of the incubation period, the tissues were fixed in formalin and examined histologically. Lesional skin continued to express features of psoriatic plaque, which included irregularly shaped epithelial cells arranged in a disorganized fashion, and elongation of the rete ridges with a thickening in their lower portion. Abnormal epidermal differentiation and separation of the upper epidermal layers from the lower layers was also a consistent feature. In contrast, nonlesional skin from psoriatic patients exhibited a histological appearance which resembled that of site-matched normal skin. When normal skin was exposed to a growth-factor-enriched culture medium during the 8-day incubation period, it exhibited a histological appearance similar to that of psoriatic skin. In addition to abnormal histological features, the psoriatic skin in organ culture released higher amounts of matrix metalloproteinase-9 (MMP-9; 92-kD gelatinase B/type IV collagenase) into the culture fluid than either nonlesional skin or normal skin. Organ cultures of psoriatic lesional skin from 6 individuals were maintained for 8 days in the presence of an antibody to the human epidermal growth-factor (EGF) receptor. The abnormal histological features of the psoriatic tissue were partially ameliorated in the presence of the antibody. These data suggest that growth factors which act through the EGF receptor help to maintain the psoriatic phenotype in organ culture. They also suggest that organ culture may provide a useful tool with which to elucidate the pathophysiological mechanisms of altered keratinocyte proliferation and differentiation in psoriasis.

Topics: Antibodies, Monoclonal; Collagenases; Epidermal Growth Factor; ErbB Receptors; Gelatinases; Growth Substances; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Metalloendopeptidases; Organ Culture Techniques; Phenotype; Psoriasis; Skin

p70 Ribosomal protein S6 kinase is a critical down-stream effector of a mitogen-stimulated signaling pathway that is selectively inhibited by the immunosuppressant rapamycin. The purpose of this study was to quantify S6 kinase expression in psoriatic involved, uninvolved, and normal epidermis and to characterize regulation of S6 kinase activity in cultured normal human keratinocytes. S6 kinase activity was increased 4-fold in psoriatic lesions (1.63 +/- 0.25 pmol per min per mg, n = 6), compared to nonlesional (0.44 +/- 0.12 pmol per min per mg, n = 6, p < 0.01), and normal (0.35 +/- 0.14 pmol per min per mg, n = 7, p < 0.01) epidermis. In contrast, S6 kinase mRNA and protein levels were not significantly different among psoriatic lesional, nonlesional, and normal epidermis. In keratinocytes, S6 kinase activity was stimulated 3-fold by mitogenic epidermal growth factor (EGF) receptor ligands, EGF and transforming growth factor-alpha (TGF-alpha), but not by cytokines interleukin-1alpha, tumor necrosis factor-alpha, interferon-gamma, or transforming growth factor-beta1. TGF-alpha stimulation of S6 kinase activity was inhibited in a concentration-dependent manner by rapamycin (IC50 < 0.2 nM) and the specific EGF receptor antagonist PD153035 (IC50 = 20 nM). Rapamycin also inhibited EGF-stimulated proliferation of keratinocytes (IC50 = 0.2 ng per ml) with a potency similar to that reported for inhibition of T-cell proliferation. We conclude: (i) the mitogenic signaling pathway(s) regulating S6 kinase is activated in psoriatic lesions, thus accounting for increased S6 kinase activity in the absence of increased S6 kinase gene or protein expression; (ii) S6 kinase activation in lesional keratinocytes likely occurs in response to EGF receptor stimulation by TGF-alpha and/or amphiregulin, which are known to be elevated in psoriatic lesions; and (iii) keratinocyte as well as T-cell mitogenic signaling pathways are susceptible to inhibition by rapamycin, suggesting that rapamycin may be of therapeutic benefit in the treatment of psoriasis.

Topics: Adult; Cell Division; Cells, Cultured; Enzyme Activation; Epidermal Growth Factor; ErbB Receptors; Humans; Immunosuppressive Agents; Keratinocytes; Polyenes; Protein Serine-Threonine Kinases; Psoriasis; Ribosomal Protein S6 Kinases; RNA, Messenger; Sirolimus; Skin; Transforming Growth Factor alpha

DNA synthesis is significantly more stimulated in response to insulin-like growth factor I (IGF-I) in growth-arrested cultures of psoriatic than of nonpsoriatic keratinocytes. Epidermal growth factor (EGF), by itself only a weak stimulator, was recently found to cause a strong synergetic effect when added together with IGF-I to newborn human keratinocytes.. (1) To measure this effect in cultured adult psoriatic and nonpsoriatic keratinocytes, and (2) to examine whether the difference in DNA synthesis after IGF-I addition could be due to differences in the binding of this growth factor.. 3H-deoxythymidine incorporation and 125I-IGF-I binding studies.. Psoriatic keratinocytes demonstrate a considerably stronger response to the combination of EGF and IGF-I than nonpsoriatic keratinocytes. This is apparently not caused by differences in binding of IGF-I.. Differences in the proliferative rate of normal and psoriatic keratinocytes may be in part due to differences in signal transduction distal from the IGF-I receptor or in the cooperation of the EGF and the IGF-I receptor.

Topics: Adult; Aged; Cells, Cultured; DNA; Drug Synergism; Epidermal Growth Factor; Humans; Insulin-Like Growth Factor I; Keratinocytes; Middle Aged; Psoriasis

Psoriasis is characterized by hyperproliferation and impared differentiation of epidermal keratinocytes (KCs). Psoriasis can be treated with derivatives of retinoic acid (RA) and vitamin D3. Analogues of vitamin D3 are able to inhibit proliferation and stimulate differentiation of KCs. In contrast, RA inhibits terminal differentiation of KCs. Interactions are known to occur between RA and vitamin D3 signalling pathways. The purpose of the present study was to determine the effect of all-trans RA on the binding of 1,25-dihydroxy-vitamin D3 (1,25 (OH)2D3) to the vitamin D3 receptor (VDR) of cultured human KCs. Cultured KCs from normal adults were incubated with or without RA (10-9-10-7M) for 4-24 h. Cells were then harvested, homogenized and ultrasonicated. The extracted protein was incubated with 3H-1,25 (OH)2D3 (0.015-1.0 nM) with or without 250-fold excess nonradioactive 1,25 (OH)2D3 for 24 h and specific binding was determined by use of the dextran coated charcoal binding assay. Western blot analysis utilizing the monoclonal antibody 9A7 gamma to VDR was performed on protein extracted from the KCs. The bands resulting from Western blot analysis were visualized by enhanced chemiluminescence. From Scatchard analysis it was found that KCs bind 1,25 (OH)2D3 with high affinity (Kd = 0.175 nM). This binding was dose and time dependently inhibited by RA (60% inhibition at 10-7 M after 24 h of incubation). By Western blot analysis, RA had no effect on the amount of protein extracted from KCs at any of the RA concentrations tested. In conclusion, these results show that binding of vitamin D3 to its receptor of human KCs can be inhibited markedly by RA without effecting the amount of protein. These results are in contrast to results with other cell types in which RA upregulates binding of 1,25 (OH)2D3 to the VDR. Because interaction between retinoids and vitamin D3 may occur at different levels during signal transduction, it is not possible to predict from our results whether RA will inhibit the effects of vitamin D3 in vivo.

Topics: Calcitriol; Cells, Cultured; Dose-Response Relationship, Drug; Epidermal Growth Factor; Humans; Keratinocytes; Kinetics; Pituitary Hormones; Protein Binding; Psoriasis; Receptors, Calcitriol; Tretinoin

Epidermal growth factor receptors (EGF-Rs) are elevated in active human psoriatic lesions, but decrease in resolving lesions. Similar biologic responses in EGF-R levels have been demonstrated within human psoriatic skin grafted onto mice. We tested the hypothesis that flaky-skin mice (fsn/fsn), one proposed genetic animal model of psoriasis, would display EGF-R levels comparable to human psoriatic epidermis and show similar biologic responses. EGF-R levels were characterized in unperturbed sites in fsn/fsn skin and +/? skin by enzyme-linked immunosorbent assay, 125I-EGF binding, and immunostaining. Altered EGF-R levels were noted after mild trauma (tape stripping) or under resolving conditions (30 doses of 50 mJ/CM2 ultraviolet B, 2.5 mg/kg oral cyclosporin A, or daily 30 microg/ml topical EGF). Increased EGF-R immunostaining was observed in involved flaky epidermal sites before treatment. To determine whether a hyperproliferative (Koebner) reaction could be induced, we tape stripped fsn/fsn tail and non-flaky dorsal sites. EGF-R levels in dorsal epidermis increased by days 3-4 after injury by enzyme-linked immunoabsorbent assay methods. When fsn/fsn mice received one of three different treatments for 6 weeks, the skin returned to a normal phenotype both grossly and microscopically. Immunoreactive EGF-R in treated, but not untreated, sites decreased to either normal or nondetectable levels. These data indicate that fsn/fsn mice exhibit an EGF-R profile identical to that of lesional and nonlesional human psoriatic epidermis. Modulations of the flaky phenotype in response to injury and three different treatments suggest that fsn/fsn is a useful in vivo model for examining new treatment modalities for psoriasiform skin diseases.

Topics: Animals; Cyclosporine; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; ErbB Receptors; Immunohistochemistry; Mice; Mice, Mutant Strains; Psoriasis; Skin; Ultraviolet Rays; Wounds and Injuries

Calcitriol or 1.25 (OH)2-vitamin D3 is used in the treatment of psoriasis as an inhibitor of cell proliferation. We studied the action of calcitriol ex vivo on the growth of psoriatic and normal human keratinocytes, and on the expression of the EGF receptor. Third passaged normal and psoriatic keratinocytes were seeded (10(4)/cm2) in 24-well dishes in serum-free medium (MCDB supplemented with amino acids, with either 0.1 or 1.1 mM of calcium) and 10(-9) M calcitriol. When subconfluence was reached, cell counts and 125I-EGF binding studies were performed. Cell counts showed at least a 50% decrease in growth under all conditions studied (normal or psoriatic keratinocytes; 0.1 or 1.1 mM calcium) when calcitriol was added. 125I-EGF binding studies showed a decrease in total receptor numbers in the presence of calcitriol with acceleration of binding at low concentrations of 125I-EGF. Scatchard plot analysis showed only one type of high affinity receptor. Receptor sites were decreased (30% to 40% of controls) in the presence of calcitriol together with a decrease in the dissociation constant. In conclusion, at almost physiological concentrations ex vivo, calcitriol strongly decreased normal and psoriatic keratinocyte growth. This potent antiproliferative effect could in part be explained by the capacity of calcitriol to downregulate EGF receptor expression.

Topics: Calcitriol; Calcium; Case-Control Studies; Cell Division; Cells, Cultured; Epidermal Growth Factor; ErbB Receptors; Humans; Keratinocytes; Middle Aged; Psoriasis

The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for KGFR in porcine burns revealed strong expression of KGFR on hair follicles and basal epidermis, confirming direct rKGF action on follicular as well as epidermal keratinocytes. Although the epithelial proliferation induced by rKGF resulted in marked neoepidermal psoriasiform hyperplasia with exaggerated rete ridges and neoepidermal and follicular maturation as assessed by expression of cytokeratin 10, a marker of keratinocyte terminal differentiation was not delayed and appeared to be accelerated i

Topics: Administration, Topical; Animals; Becaplermin; Burns; Cell Division; Epidermal Growth Factor; Epithelium; Fibroblast Growth Factor 10; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Glycoproteins; Growth Substances; Hyperplasia; In Situ Hybridization; Integrins; Keratinocytes; Neuregulins; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Psoriasis; Recombinant Proteins; Swine; Wound Healing

Glycosaminoglycan-modified isoforms of CD44 have been implicated in growth factor presentation at sites of inflammation. In the present study we show that COS cell transfectants expressing CD44 isoforms containing the alternatively spliced exon V3 are modified with heparan sulfate (HS). Binding studies with three HS-binding growth factors, basic-fibroblast growth factor (b-FGF), heparin binding-epidermal growth factor (HB-EGF), and amphiregulin, showed that the HS-modified CD44 isoforms are able to bind to b-FGF and HB-EGF, but not AR. b-FGF and HB-EGF binding to HS-modified CD44 was eliminated by pretreating the protein with heparitinase or by blocking with free heparin. HS-modified CD44 immunoprecipitated from keratinocytes, which express a CD44 isoform containing V3, also bound to b-FGF. We examined whether HS-modified CD44 isoforms were expressed by activated endothelial cells where they might present HS-binding growth factors to leukocytes during an inflammatory response. PCR and antibody-binding studies showed that activated cultured endothelial cells only express the CD44H isoform which does not contain any of the variably spliced exons including V3. Immunohistological studies with antibodies directed to CD44 extracellular domains encoded by the variably spliced exons showed that vascular endothelial cells in inflamed skin tissue sections do not express CD44 spliced variants. Keratinocytes, monocytes, and dendritic cells in the same specimens were found to express variably spliced CD44. 35SO4(-2)-labeling experiments demonstrated that activated cultured endothelial cells do not express detectable levels of chondroitin sulfate or HS-modified CD44. Our results suggest that one of the functions of CD44 isoforms expressing V3 is to bind and present a subset of HS-binding proteins. Furthermore, it is probable that HS-modified CD44 is involved in the presentation of HS-binding proteins by keratinocytes in inflamed skin. However, our data suggests that CD44 is not likely to be the proteoglycan principally involved in presenting HS-binding growth factors to leukocytes on the vascular cell wall.

Topics: Alternative Splicing; Antibodies, Monoclonal; Base Sequence; Carrier Proteins; Dermatitis, Allergic Contact; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Exons; Fibroblast Growth Factor 2; Flow Cytometry; Genetic Variation; Growth Substances; Heparin-binding EGF-like Growth Factor; Heparitin Sulfate; Hyaluronan Receptors; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Ligands; Molecular Sequence Data; Polymerase Chain Reaction; Psoriasis; Receptors, Cell Surface; Receptors, Lymphocyte Homing; Recombinant Fusion Proteins; RNA, Messenger

The aim of the present study was to investigate the distribution of Langerhans cells and T cells in the lesions and also the phenotypic expression of markers of activation on lesional T cells and keratinocytes, before and after 2 weeks of topical treatment of 7 psoriatic patients with calcipotriol. Before treatment, the infiltrate was composed mainly of T cells and there was decreased expression of CD1 on the intra-epidermal Langerhans cells. ICAM-1 and EGF receptor were present throughout the epidermis, but keratinocytes expressing Transferrin receptor were detected only in the basal layer. After 14 days of calcipotriol therapy, there were significantly fewer CD4T cells in the dermis and an increased number of intraepidermal CD1 + Langerhans cells. ICAM-1 expression on lesional keratinocytes was reduced in all patients, but the expression of EGF receptor was decreased in 3 patients only, and Transferrin receptor expression on keratinocytes had not changed. All these changes were concurrent with moderate clinical improvement of the lesions. The results suggest that in the early stages of the clinical response to calcipotriol there is an immunomodulating effect of the drug associated with variable decreases in keratinocyte expression of markers of activation.

Topics: Administration, Topical; Adult; Calcitriol; Cell Adhesion Molecules; Dermatologic Agents; Epidermal Growth Factor; HLA-DR Antigens; Humans; Immunohistochemistry; Intercellular Adhesion Molecule-1; Keratinocytes; Langerhans Cells; Middle Aged; Ointments; Psoriasis; Skin; T-Lymphocyte Subsets

Psoriasis vulgaris has been recognized lately as an immunologically mediated inflammatory skin disease. To analyze the pathogenetic role of T lymphocytes in the generation of psoriatic skin lesions, 105 T cell clones (TCC) and 10 T cell lines (TCL) were differentially isolated from dermis and epidermis of psoriatic skin specimens. Supernatants prepared from these T cells were studied for their effects on keratinocyte proliferation in vitro. Conditioned media from 14 of 77 epidermal TCC, 7 of which were CD8+, and from 8 of 28 dermal TCC, 5 of which were CD8+, reproducibly enhanced keratinocyte proliferation, with more pronounced mitogenic activities found in dermal TCC. Another 9 epidermal and 3 dermal TCC did not affect keratinocyte growth and supernatants from the remaining clones, as well as from the 5 epidermal and 5 dermal TCL, inhibited keratinocyte replication to varying degrees. Both mitogenic and suppressive activities were largely abolished by addition of an antiserum to interferon-gamma (IFN-gamma), while addition of epidermal growth factor or irradiated psoriatic TCL had little effect on the activities of the supernatants. These studies reveal that a subpopulation of lesional psoriatic T lymphocytes is capable of enhancing keratinocyte proliferation in vitro via secreted products. Their mitogenic capacity most likely requires IFN-gamma, but the ultimate effect is apparently determined by the presence of additional cytokines. Activation of T cells secreting such combinations of factors in vivo may contribute to the keratinocyte alterations characteristic of psoriatic skin lesions.

Topics: Cell Division; Epidermal Cells; Epidermal Growth Factor; Humans; In Vitro Techniques; Interferon-gamma; Keratinocytes; Lymphokines; Mitogens; Psoriasis; Skin; T-Lymphocytes

Interleukin-6 (IL-6) is a multifunctional cytokine which has been suggested to function as an autocrine mitogen in psoriatic epidermis. We report here the results of several experiments designed to further examine this hypothesis. Blot hybridization was unable to detect 1.3 kb IL-6 transcripts in RNA extracted from normal or psoriatic epidermal (keratome) biopsies, suggesting that IL-6 expression is very low in normal and psoriatic epidermis. Therefore, qualitative and semiquantitative PCR/Southern blot analyses were performed on keratome-derived RNA, and revealed variable but significantly increased IL-6 mRNA levels in lesional psoriatic relative to normal tissue. To further examine the ability of normal human keratinocytes (NHK) to express IL-6, RNA was extracted from rapidly proliferating secondary NHK cultures. IL-6 transcripts were nearly undetectable by blotting in keratinocytes grown in low-calcium serum-free medium, but low levels could be induced by treatment with 1.8 mM CaCl2. IL-6 transcripts were strongly superinduced after cycloheximide treatment, suggesting that a labile protein regulates IL-6 mRNA levels in these cells. Finally, the mitogenic activity of IL-6 was examined in NHK under varying conditions of cell density and added growth factors. IL-6 did not stimulate high density keratinocyte growth in the presence or absence of other growth factors, but did stimulate clonal growth in epidermal growth factor (EGF)-deficient media at high concentrations (> or = 10 ng/ml). The proliferative effects of IL-6, but not of basic fibroblast growth factor, were abrogated by monoclonal antibodies directed against the EGF receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Base Sequence; Cell Division; Cells, Cultured; Epidermal Growth Factor; Humans; Interleukin-6; Keratinocytes; Molecular Sequence Data; Nucleic Acid Hybridization; Psoriasis; RNA, Messenger

Insulin-like growth factor I (IGF-I)/somatomedin C is an important mediator of keratinocyte growth in vitro, and the expression of IGF-I receptors in the basal layer of normal epidermis suggests that this growth pathway may function in the regulation of keratinocyte growth in vivo as well. The pattern of IGF-I receptor expression in normal skin is distinct from that of the epidermal growth factor (EGF) receptor, suggesting that these receptors might be differentially regulated. The purpose of this study was to obtain a better understanding of IGF-I receptor function in the skin by examining IGF-I receptor expression in psoriatic epidermis and in cultured human keratinocytes. Our findings indicate that IGF-I receptor expression is increased in psoriasis as measured by protein tyrosine kinase assays of biopsy extracts and by immunohistochemical staining with an IGF-I receptor-specific monoclonal antibody. Unlike EGF receptor expression, which is also increased in psoriatic epidermis, the pattern of IGF-I receptor expression corresponds closely with the increased size of the keratinocyte proliferative compartment in psoriasis. Biochemical agents that diminish EGF receptor ligand binding (phorbol ester or calcium ionophore treatment) produce opposite effects on the IGF-I receptor. These results suggest that cellular expression and differential regulation of both growth factor receptor systems may control critical aspects of epidermal proliferation or function.

Topics: Antibodies, Monoclonal; Calcimycin; Epidermal Growth Factor; Epidermis; ErbB Receptors; Humans; Insulin-Like Growth Factor I; Keratinocytes; Precipitin Tests; Protein Kinases; Psoriasis; Receptors, Cell Surface; Receptors, Somatomedin; Tetradecanoylphorbol Acetate

Active psoriatic lesions have increased EGF/TGF alpha receptors, historically known as the EGF-R. This increase is due to their persistence into the outer parakeratotic layers as measured by autoradiography, immunohistochemistry, and mRNA assays. When psoriatic lesions in patients resolve due to therapy with different modalities, the EGF-R persistently expressed in the outer layers of the epidermis either disappear or resume a basal location presumably due to receptor downregulation. To test whether EGF could downregulate EGF-R and biologically affect psoriatic epidermis, split-thickness skin grafts of active psoriatic lesions were sutured onto the dorsal surface of nude mice. After 3 weeks, the mice were treated daily for a 6-week period with placebo, or 10 or 50 micrograms/ml EGF. Immunostaining showed persistent EGF-R in all epidermal layers in the untreated, placebo-, and 10 micrograms/ml EGF-treated groups. Those grafts receiving a high dose of EGF (50 micrograms/ml) showed either no immunoreactive EGF-R or faint basilar staining. As an additional check for functional activity of the EGF-R, an abundant substrate for this receptor, PLC-gamma 1 was also evaluated following EGF treatment. A similar distribution and modulation pattern following treatment were observed in the grafts immunostained for PLC-gamma 1, suggesting that exogenous EGF treatment affected metabolic pathways subsequent to ligand receptor binding. Morphologic alterations characteristic of a regressing psoriatic phenotype (a decrease in acanthosis, thickness, and the resumption of the orthokeratotic mode of differentiation) were noted in those lesions receiving the 50 micrograms/ml EGF treatment. This study indicates that persistent EGF-R in psoriasis vulgaris are biologically active in vivo and may serve a pivotal role in the regulation of psoriatic lesions.

Topics: Administration, Topical; Animals; Epidermal Growth Factor; ErbB Receptors; Humans; Mice; Mice, Nude; Psoriasis; Skin; Type C Phospholipases

Epidermal growth factor (EGF) levels in the urine of 31 normal individuals and 33 psoriatic patients were measured. The amounts of urinary EGF secreted in a day by normal and psoriatic individuals were not significantly different nor were the levels of EGF in random urine specimens corrected for creatinine values. It is known that the urinary EGF content corrected for the creatinine value correlates very well with the EGF level in blood as well as in 24-h urine specimens. Our data indicate that EGF circulating in the blood may not be correlated with the extent of psoriatic lesions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Psoriasis

Epidermal growth factor (EGF) may have a modulatory role in renal growth and function. The aim of the present study was to evaluate whether urinary excretion of EGF is altered in psoriatic patients with or without arterial hypertension. The glomerular filtration rate was similar in psoriatics as compared with age- and sex-matched controls, whereas urinary EGF (microgram/g creatinine) was significantly reduced in psoriatics: normotensive subjects, 29.52 +/- 3.51 (psoriatics) versus 44.31 +/- 1.20 (controls, p less than 0.05); hypertensive subjects, 19.67 +/- 3.96 (psoriatics) versus 30.11 +/- 1.52 (controls, p less than 0.05). The urinary EGF excretion was lower in males than in females, save for hypertensive psoriatics. Urinary EGF correlated inversely with age and directly with urinary kallikrein excretion. Urinary kallikrein activity was reduced and microalbuminuria increased in hypertensive psoriatics. These alterations might suggest that initial deterioration of renal function is present in psoriasis.

Topics: Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Hypertension; Kallikreins; Kidney; Male; Middle Aged; Psoriasis; Sex Factors

One of the more prominent clinical treatments for skin diseases such as psoriasis and vitiligo involves the use of a combination of psoralens and UV light, a procedure referred to as PUVA chemotherapy. This drug regimen markedly alters epidermal cell growth and differentiation. In many cell types, an early cellular event following treatment of cells with PUVA is inhibition of binding of epidermal growth factor (EGF) to its receptor. To examine the mechanism underlying this effect, we used A431 cells, a human epidermal cell line known to express large numbers of EGF receptors. We found that exposure of A431 cells to PUVA caused a dramatic inhibition of EGF-stimulated EGF receptor tyrosine kinase activity. Inhibition required intact cells and did not appear to be mediated by protein kinase C, because this inhibition was apparent in cells in which the enzyme was down-regulated by phorbol ester pretreatment and in cells treated with inhibitors of protein kinase C. Inhibition of tyrosine kinase activity by PUVA was distinct from other inhibitors of EGF receptor function in that it was associated with a rapid increase in the amount of phosphate incorporated into serine residues of the EGF receptor. This suggested that PUVA-induced serine phosphorylation may mediate EGF receptor kinase activity. These results demonstrate that alterations in EGF receptor function may contribute to the therapeutic efficacy of PUVA in photo-chemotherapy.

Topics: Cell Line; Epidermal Growth Factor; ErbB Receptors; Humans; Phosphorylation; Protein Kinase C; Protein-Tyrosine Kinases; Psoriasis; PUVA Therapy; Tetradecanoylphorbol Acetate

Using 125I-EGF the distribution of EGF receptors in psoriatic epidermis was autoradiographically examined. Binding sites of 125I-EGF (20 ng/ml) were mainly located at basal and suprabasal cells in normal and uninvolved psoriatic epidermis, whereas they were located at spinous cells as well as at basal and suprabasal cells in affected psoriatic epidermis. Binding of 125I-EGF (1 ng/ml), on the other hand, was observed in normal and uninvolved psoriatic epidermis but not in affected psoriatic epidermis. The majority of EGF receptors in affected psoriatic epidermis were featured by low affinity for EGF.

Topics: Autoradiography; Epidermal Growth Factor; Epidermis; ErbB Receptors; Humans; Keratinocytes; Psoriasis

Over a period of 4 years, 20 patients suffering from severe forms of psoriasis (erythrodermic, sub-erythrodermic, resistant generalized forms and/or forms associated with acute arthropathy) were treated with 96 h of continuous i.v. infusion of somatostatin (Stilamin, Serono) diluted in D5W at 250 micrograms/h. In addition to the usual blood chemistry parameters, circadian levels of growth hormone (GH) and epidermal growth factor (EGF) were measured before, during, and after therapy. Approximately 2-3 weeks after termination of therapy, erythrodermic and suberythrodermic symptoms had disappeared. In some patients, a few lesions of psoriasis vulgaris remained, although they were much less severe. Remission of acute arthropathy was impressive. Blood chemistry parameters were unchanged after therapy. Circadian levels of GH and EGF, normal before therapy, were significantly decreased after therapy. The infusion was well-tolerated. Infusion rates of greater than 250 micrograms/h caused only some complaints of abdominal pain, nausea, and vomiting. During the 4 years, erythrodermic symptoms reappeared only in seven patients, three of whom were also arthropathic. After 6-8 months, they underwent a second course of somatostatin therapy with good results. The other patients are still able to control their disease with tar-based products alone or with low-dose 8-methoxypsoralen + UVA (PUVA) or UV therapy. The arthropathic patients control their symptoms with periodic low-dose nonsteroidal antiinflammatory drug therapy.

Topics: Epidermal Growth Factor; Female; Growth Hormone; Humans; Infusions, Intravenous; Male; Psoriasis; Recurrence; Somatostatin

Topics: Coal Tar; DNA; Epidermal Growth Factor; Erythema; Humans; Psoriasis; PUVA Therapy; Skin; Ultraviolet Rays

Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyperproliferative disease such as psoriasis vulgaris is unclear. To study the pathogenesis of psoriasis, 4-mm2 punch biopsy specimens of normal, uninvolved, and involved psoriatic skin were assayed for EGF receptors by autoradiographic, immunohistochemical, and biochemical methods. Using autoradiographic and immunohistochemical methods, basal keratinocytes were found to contain the greatest number of EGF binding sites and immunoreactive receptors as compared to the upper layers of the epidermis in both normal epidermis and psoriatic skin. No EGF receptor differences between normal and psoriatic epidermis were observed in this layer. In the upper layers of the epidermis, a 2-fold increase in EGF binding capacity was observed in psoriatic skin as compared with normal thin or thick skin. Biochemical methods indicated that [125I]EGF binding was increased in psoriatic epidermis as compared with similar thickness normal epidermis when measured on a protein basis. Epidermal growth factor was shown to increase phosphorylation of the EGF receptor in skin. EGF receptors retained in the nonmitotic stratum spinosum and parakeratotic stratum corneum may reflect the incomplete, abnormal differentiation that occurs in active psoriatic lesions. Alternatively, retained EGF receptors may play a direct role in inhibiting cellular differentiation in the suprabasal layers.

Topics: Autoradiography; DNA; Epidermal Growth Factor; ErbB Receptors; Humans; In Vitro Techniques; Iodine Radioisotopes; Phosphorylation; Protein-Tyrosine Kinases; Psoriasis; Receptors, Cell Surface; Skin

Protein tyrosine kinase and protein phosphotyrosine phosphatase activities were measured in extracts of skin samples from patients with psoriasis. Both kinase and phosphatase activities were significantly greater in samples taken from an involved area, characterized by epidermal hyperproliferation, than from adjacent skin of normal appearance. Samples from skin of non-psoriatic individuals were indistinguishable from the normal-appearing skin of psoriatic patients. There was no detectable change in the apparent Km for either ATP or casein of the protein tyrosine activity in plaques compared with controls. Phosphorylation of endogenous proteins was also increased about 2-fold in plaque extracts compared with controls. Both epidermal growth factor and platelet-derived growth factor stimulated endogenous protein tyrosine phosphorylation in particulate fractions of plaque biopsies but not in solubilized extracts nor in any control fractions. Our data suggest that increased protein tyrosine phosphorylation and dephosphorylation activity and growth factor sensitivity are important factors in non-malignant hyperplastic cell growth.

Topics: DNA; Epidermal Growth Factor; Humans; Kinetics; Phosphoprotein Phosphatases; Platelet-Derived Growth Factor; Protein Kinases; Protein-Tyrosine Kinases; Psoriasis; Skin

Topics: Adult; Blood Proteins; Cell Division; Depression, Chemical; Epidermal Growth Factor; Humans; In Vitro Techniques; Lymphocyte Activation; Phytohemagglutinins; Psoriasis

Topics: Depression, Chemical; Epidermal Growth Factor; Humans; Psoriasis; Somatostatin

A radioreceptor assay for human epidermal growth factor-urogastrone (EGF-URO) employing mouse EGF-URO as tracer and calibration standards and human placental receptor as binding protein is compared with a radioimmunoassay for human EGF-URO. Results employing the receptor assay indicated similar values for urinary concentrations (1-16 nmol/l) for healthy control subjects and for patients with psoriasis. Lower values were obtained for bed-ridden patients with burns or patients recovering from orthopaedic surgery. The results obtained by radioimmunoassay were somewhat higher and correlated poorly (r = 0.5) with those obtained with the radioreceptor assay. The reason for this discrepancy is discussed.

Topics: Adult; Aged; Burns; Epidermal Growth Factor; Evaluation Studies as Topic; Humans; Immobilization; Male; Middle Aged; Psoriasis; Radioimmunoassay; Radioligand Assay

Topics: Animals; Autoradiography; Bone Marrow Cells; Carcinoma, Squamous Cell; Cell Count; Cell Division; Cells, Cultured; Diffusion; DNA; Epidermal Cells; Epidermal Growth Factor; Epidermis; Growth Inhibitors; Humans; Interferons; Mice; Peptides; Psoriasis; Skin Neoplasms