cyclin-d1 and Psoriasis

Cyclosporin induces a dramatic reversal to normality in psoriatic lesions, with a reduction of inflammatory infiltrate and epidermal proliferation. It is known that the cell cycle and cell proliferation are regulated by the sequential activation of cyclin-dependent kinase/cyclin complexes.. We evaluated epidermal cell turnover and thickness, as well as the expression of cyclins D1, B and A in psoriatic skin before and after therapy with cyclosporin.. Epidermal thickness, mitotic and apoptotic indices (MI, AI), as well as the percentages of epidermal cell nuclei positive for Ki-67 and cyclins D1, B and A were calculated. Cytoplasmic positivity to cyclin B was also evaluated.. After 6 weeks of therapy, we observed a clinical improvement of the disease and normalization of the epidermis. Epidermal thickness and Ki-67-, cyclins B- and A-positive nuclei percentage were significantly higher before therapy than after (0.52 +/- 0.05 mm vs. 0.21 +/- 0.03 mm, P < 0.001; 19 vs. 2.6, 19 vs. 3, and 12 vs. 1, respectively; P < 0.0005); cytoplasmic positivity to cyclin B was slightly higher before therapy (score 3 vs. 2-3). Cyclin D1 was negative or expressed in a low percentage of nuclei in psoriasis before therapy (0.78), whereas it was always negative after therapy. MI was 0.15 before therapy, whereas mitoses were almost absent afterwards. Apoptoses were undetectable before therapy, whereas a few apoptoses were observed after treatment (AI = 0.4).. Overexpression of cyclins B and A, rather than D1 seems to characterize psoriasis. Their evaluation could provide further insights in understanding the development of this disorder and could be used to verify the efficacy of currently used therapies as well as future ones.

Topics: Adult; Biomarkers; Cell Division; Cyclin A; Cyclin B; Cyclin D1; Cyclins; Cyclosporine; Dermatologic Agents; Epidermis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Psoriasis

Psoriasis is a skin disease characterized by abnormal keratinocyte proliferation and inflammation. Currently, there are no cures for this disease, so the goal of treatment is to decrease inflammation and slow down the associated rapid cell growth and shedding. Recent advances have led to the usage of phosphodiesterase 4 (PDE4) inhibitors for treatment of this condition. For example, apremilast is an oral, selective PDE4 inhibitor that is able to reduce skin inflammation and is Food and Drug Administration (FDA)-approved to treat adults with moderate to severe psoriasis and/or psoriatic arthritis. However, common target-related adverse events, including diarrhea, nausea, headache, and insomnia limit the usage of this drug. To circumvent these effects, the usage of PDE4 inhibitors specifically designed for topical treatment, such as CHF6001, may combine local anti-inflammatory activity with limited systemic exposure, improving tolerability. In this study, we showed that CHF6001, currently undergoing clinical development for COPD, suppresses human keratinocyte proliferation as assessed via BrdU incorporation. We also observed decreased re-epithelialization in a scratch-wound model after CHF6001 treatment. At the molecular level, CHF6001 inhibited translocation of phosphorylated NF-κB subunit p65, promoting loss of nuclear cyclin D1 accumulation and an increase of cell cycle inhibitor p21. Furthermore, CHF6001 decreased oxidative stress, measured by assessing lipid peroxidation (4-HNE adduct formation), through the inactivation of the NADPH oxidase. These results suggest that CHF6001 has the potential to treat skin disorders associated with hyperproliferative keratinocytes, such as psoriasis by targeting oxidative stress, abnormal re-epithelization, and inflammation.

Topics: Aldehydes; Cell Line; Cell Proliferation; Cell Survival; Cyclin D1; Humans; Keratinocytes; Lipid Peroxidation; NADPH Oxidases; Oxidative Stress; para-Aminobenzoates; Phosphodiesterase 4 Inhibitors; Psoriasis; Sulfonamides; Transcription Factor RelA

Psoriasis is a hyperproliferative inflammatory skin disease; therefore, it is highly likely that psoriatic skin lesions may transform into malignancies. However, malignant transformation is not common. We performed immunohistochemical studies using anti‑cyclin D1, anti‑cyclin E, anti‑pRb, anti‑p53, anti‑p16INK4a, and anti‑Ki‑67 antibodies in normal skin, psoriatic epidermal tissue, and squamous cell carcinoma (SCC) tissue. Furthermore, western blot analysis and immunohistochemical staining were performed to ascertain differences in cyclin D1, cyclin E, pRb, and Ki‑67 expression before and after treatment for psoriasis. Cyclin D1 expression was higher in chronic psoriatic lesions than that in normal epidermis. Psoriasis lesions showed a strong intensity of positive nuclear staining for cyclin D1 among several normally stained nuclei in the basal layer. Cyclin E expression in psoriasis was stronger in the granular and spinous layer than in the normal epidermis. Expression levels of pRb and p53 were found to be higher in the psoriasis group compared with the normal epidermis. Total basal layer cell counts for p53WT expression were found to be significantly higher in the psoriasis group compared with the normal group. However, p16 expression was very weak in the normal and psoriasis groups compared with that in the SCC group. Ki‑67 immunoreactivity was significantly higher in psoriasis compared with normal epidermis and was similar with that in the SCC group. According to immunohistochemistry and immunoblot analysis, the expression levels of cyclin D1, cyclin E, pRb, and Ki‑67 in psoriasis lesions decreased after treatment and were similar with those in the normal group. Thus, increased expression of cyclin D1 and cyclin E may be involved in cell cycle progression in psoriatic epidermis, and pRb and p53 may play important roles in the prevention of malignant transformation under the hyperproliferative state in psoriasis.

Topics: Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cyclin D1; Cyclin E; Female; Gene Expression Regulation; Humans; Inflammation; Ki-67 Antigen; Male; Psoriasis; Retinoblastoma Protein; Skin; Tumor Suppressor Protein p53

Psoriasis is one of the most common inflammatory skin disorders, affecting 3% of the general population. Terminalia chebulanin (TC) is a polyphenolic compound that possesses antioxidant and anti-inflammatory activities. The current study was designed to investigate the effect of TC on psoriatic lesions.. We examined the protective effect of TC against psoriatic lesions in mice and keratinocyte proliferation in HaCaT cells.. We found that TC exhibited potent anti-psoriatic activities, as evidenced by improvement of erythema and scaling scores, decrease of epidermal, ear and skinfold thickening, decrease of tumor necrosis factor α (TNFα), interleukin (IL)-17A, IL-23 and matrix metalloproteinase (MMP)-9 expression, and decrease of TBARS content and increase of GSH content in IMQ-treated mice, and decrease of keratinocyte proliferation, TNFα, IL-17A and IL-23 expression, and ROS level in M5-treated cells. All those effects induced by TC were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of heme oxygenase (HO)-1, indicating that HO-1 was responsible the anti-psoriatic effect of TC. Moreover, TC inhibited the upregulation of p65 NF-x03BA;B under in vitro psoriatic condition. ZnPP suppressed TC-induced inhibition of p65 NF-x03BA;B expression. Overexpression of p65 NF-x03BA;B significantly suppressed TC-induced decrease of TNFα, IL-17A and IL-23 expression and keratinocyte proliferation, indicating that HO-1-mediated downregulation of NF-x03BA;B was involved in the anti-psoriatic effect of TC.. The data demonstrate that TC may serve as a potential therapeutic option for psoriatic patients.

Topics: Animals; Blotting, Western; Cell Line; Cell Proliferation; Cyclin D1; Cyclin E; Enzyme Inhibitors; Heme Oxygenase-1; Humans; Hydrolyzable Tannins; Interleukin-17; Interleukin-23; Keratinocytes; Male; Matrix Metalloproteinase 9; Mice, Inbred BALB C; Phytotherapy; Protoporphyrins; Psoriasis; Reverse Transcriptase Polymerase Chain Reaction; Skin; Terminalia; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Psoriasis vulgaris (PV) is characterized by keratinocyte hyperproliferation. Altered expression of cell-cycle regulatory genes involved in the cyclin D1 ⁄ p16 INK4-pRb pathway may contribute to this epidermal hyperproliferation.. To assess the expression of cyclin D1 and p16 in psoriasis, and to evaluate the effect of phototherapy on their expression.. The study population comprised 25 patients with PV and 10 healthy controls. Patients were treated with 24 sessions of either narrowband ultraviolet (UV) B or psoralen UVA. Skin biopsies were taken from the affected skin of each patient before and after treatment, and from the healthy controls, to examine cyclin D1 and p16 expression.. Before phototherapy, the mean value of cyclin D1 concentration in patients was significantly greater than that in controls and the mean value of p16 concentration in patients was significantly lower than that in controls. Following treatment, we detected a significant decrease in cyclin D1 and a significant increase in p16.. Cyclin D1 upregulation and p16 downregulation may play a role in the pathogenesis of psoriasis. Normalization of the levels of both parameters may be a mechanism by which phototherapy induces remission in psoriasis.

Topics: Adult; Aged; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Polymerase Chain Reaction; Psoriasis; PUVA Therapy; RNA, Messenger; Skin; Young Adult

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1) functions in both DNA repair and redox signaling, making it an attractive emerging therapeutic target. However, the role of APE1 in cutaneous inflammatory responses is largely unknown. In this study, we report that APE1 is a key upstream regulator in TLR2-dependent keratinocyte inflammatory responses. We found that nuclear expression of APE1 in epidermal layers was markedly up-regulated in psoriatic skin. APE1 was essential for the transcriptional activation and nuclear translocation of hypoxia-inducible factor-1alpha and NF-kappaB, both of which are crucial for inflammatory signaling in keratinocytes. Moreover, APE1 played a crucial role in the expression of TLR2-mediated inflammatory mediators, including TNF-alpha, CXCL8, and LL-37, in HaCaT cells and human primary keratinocytes. Silencing of APE1 attenuated cyclin D1/cyclin-dependent kinase 4 expression and phosphorylation of ERK1/2 and Akt, thereby affecting keratinocyte proliferation. Importantly, TLR2-induced generation of reactive oxygen species contributed to the nuclear translocation and expression of APE1, suggesting an autoregulatory circuit in which the subcellular localization of APE1 is associated with the production of APE1 per se through reactive oxygen species-dependent signaling. Taken together, these findings establish a role for APE1 as a master regulator of TLR2-dependent inflammatory responses in human keratinocytes.

Topics: Antimicrobial Cationic Peptides; Apoptosis; Cathelicidins; Cell Line; Cyclin D1; Cyclin-Dependent Kinase 4; DNA-(Apurinic or Apyrimidinic Site) Lyase; Epidermis; Extracellular Signal-Regulated MAP Kinases; Humans; Hypoxia-Inducible Factor 1; Inflammation; Interferon Inducers; Interleukin-8; Keratinocytes; NF-kappa B; Poly I-C; Proto-Oncogene Proteins c-akt; Psoriasis; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 2; Transcriptional Activation; Transfection; Tumor Necrosis Factor-alpha; Up-Regulation; Zymosan

The polycomb group (PcG) genes are epigenetic suppressors of gene expression that play an important role in development. In this study, we examine the role of Bmi-1 (B-cell-specific Moloney murine leukemia virus integration site 1) as a regulator of human epidermal keratinocyte survival. We identify Bmi-1 mRNA and protein expression in epidermis and in cultured human keratinocytes. Bmi-1 is located in the nucleus in cultured keratinocytes, and in epidermis it is expressed in the basal and suprabasal layers. Adenovirus-delivered Bmi-1 promotes keratinocyte survival and protects keratinocytes from stress agent-mediated cell death. This is associated with increased levels of cyclin D1 and selected cyclin-dependent kinases, and reduced caspase activity and poly(ADP-ribose) polymerase (PARP) cleavage. Bmi-1 may be involved in the maintenance of disease state, as Bmi-1 levels are elevated in transformed keratinocytes, skin tumors, and psoriasis. The presence of Bmi-1 in suprabasal non-proliferative cells of the epidermis and within a high percentage of cells within skin tumors suggests a non-stem cell pro-survival role for Bmi-1 in this tissue. Based on the suprabasal distribution of Bmi-1 in epidermis, we propose that Bmi-1 may promote maintenance of suprabasal keratinocyte survival to prevent premature death during differentiation. Such a function would help assure proper formation of the stratified epidermis.

Topics: Animals; Apoptosis; Cell Cycle Proteins; Cell Survival; Cells, Cultured; Cyclin D1; Epidermal Cells; Epidermis; Guanine Nucleotide Exchange Factors; Humans; Keratinocytes; Mice; Mice, SCID; Nuclear Proteins; Polycomb Repressive Complex 1; Proto-Oncogene Proteins; Psoriasis; Repressor Proteins; RNA, Messenger; Skin Neoplasms

To examine the expressions of E-cadherin, beta-catenin and cyclin D1 in the skin lesions of patients with psoriasis vulgaris, and understand their possible roles in keratinocyte hyperproliferation in these patients.. Immunohistochemistry was performed to detect the expressions of E-cadherin, beta-catenin and cyclin D1 in the normal skin tissues and psoriatic lesions.. In normal skin tissues, positive staining for E-cadherin and beta-catenin was detected in all layers of the normal epidermis at the sites of cell-cell junctions, and downregulation of E-cadherin and beta-catenin expression was found in the granular layer and basal layer of the psoriatic lesions. Cyclin D1 overexpression was observed mainly in the basal layer of the lesions, which was correlated to abnormal expression of beta-catenin.. Downregulation of E-cadherin and beta-catenin expression and cyclin D1 overexpression in psoriatic skin are probably involved in keratinocyte hyperproliferation in psoriasis vulgaris.

Topics: Adult; beta Catenin; Cadherins; Cyclin D1; Down-Regulation; Epidermis; Female; Humans; Immunohistochemistry; Male; Psoriasis

Human papillomavirus (HPV) is able to subvert the host cell replication machinery so as to foster viral reproduction. Specifically, HPV infection is known to induce expression of proliferation antigens such as Ki67 and proliferative cell nuclear antigen (PCNA) in differentiated keratinocytes which have ceased to replicate. In order to determine whether cyclin D1 or cyclin E deregulation is also a feature of HPV infection, an immunohistochemical investigation of cyclin D1, cyclin E, Ki67, and PCNA expression has been carried out in 38 cases of HPV 6/11-related condyloma acuminatum (CA). Results were compared with those obtained from 15 psoriatic proliferative lesions. Whereas 35 (92.1 per cent) CA samples exhibited positive nuclear immunostaining for cyclin E, no cyclin D1 immunoreaction was detected in any of the CA samples studied. All psoriatic lesions showed immunostaining for both cyclins. All CA cases revealed a positive immunoreaction for Ki67 and 33 for PCNA, both in the parabasal and in the differentiated upper epithelial layers. Parabasal keratinocytes of psoriatic lesions were always positive for both Ki67 and PCNA. These results indicate that in the onslaught of HPV 6/11 upon the keratinocyte replication machinery, cyclin E, PCNA, and Ki67 are amongst the targeted cell cycle modulators, whereas cyclin D1 is spared the main effects of virus-cell interplay. In contrast, both cyclins seem to be induced in psoriasis, a non-viral proliferative skin condition.

Topics: Cell Division; Condylomata Acuminata; Cyclin D1; Cyclin E; Humans; Immunoenzyme Techniques; In Situ Hybridization; Ki-67 Antigen; Papillomaviridae; Proliferating Cell Nuclear Antigen; Psoriasis; Skin

Because the immunosuppressant rapamycin (sirolimus) blocks T cell proliferation in G1 phase, it has been proposed as a potential treatment for psoriasis, a skin disease characterized by T cell activation and keratinocyte stem cell hyperproliferation. To determine another potentially important mechanism through which rapamycin can act as an antipsoriatic agent, we tested its direct effect on keratinocyte stem cell proliferation in vitro as well as in vivo. In vivo cell cycle quiescent (G0 phase) stem cell keratinocytes in primary culture sequentially express de novo cyclin D1 and proliferating cell nuclear antigen (PCNA), prior to S phase entry, and upregulate beta1 integrin. Rapamycin inhibited the growth of keratinocytes that were leaving quiescence as well as those already in cell cycle without affecting cell viability. Although beta1 integrin(bright) expression was not affected, the number of beta1 integrin(bright) cells entering S/G2/M was significantly lowered by rapamycin. Cells treated with rapamycin exhibited decreased PCNA expression while cyclin D1 expression, which precedes PCNA expression in the cell cycle, was not affected. We found similar effects on stem cell keratinocytes in patients with psoriasis treated systemically with rapamycin. Because PCNA is required for cell cycle progression from G1 to S phase, our data indicate that inhibition of PCNA protein synthesis may be an important regulatory element in the ability of rapamycin to exert a G1 block.

Topics: Cells, Cultured; Cyclin D1; Cyclins; Flow Cytometry; G1 Phase; Humans; Immunosuppressive Agents; Integrins; Keratinocytes; Oncogene Proteins; Polyenes; Proliferating Cell Nuclear Antigen; Psoriasis; Resting Phase, Cell Cycle; S Phase; Sirolimus; Stem Cells; Up-Regulation