calcipotriene and Inflammation

The topical treatment of psoriasis benefits from the alternate use of dermocorticosteroids and vitamin D3 analogues. A new galenic formulation allows to combine them in a single application. Dovobet (LEO Pharma) ointment is the association of calcipotriol 50 microg/g with betamethasone dipoprionate 0.5 mg/g. This formulation boosts the therapeutic activity of calcipotriol. It also decreases the irritative inflammatory reaction due to calcipotriol without increasing the atrophogenic risk of the dermocorticoid.

Topics: Administration, Topical; Betamethasone; Calcitriol; Drug Therapy, Combination; Humans; Inflammation; Psoriasis

Vitamin D3 analogs interfere with various aspects of epidermal growth, inflammation, and cellular differentiation. Most data are derived from in vitro studies. In the present review, the in vivo effects of vitamin D3 analogues on the psoriatic plaque are discussed. Calcipotriol, tacalcitol, and calcitriol in ointment modulate aspects of epidermal growth, differentiation, and inflammation. Immunohistochemical studies suggest that the inflammatory changes might be more expressed after treatment with calcitriol and tacalcitol. Flow cytometric quantification of the percentage of cells in SG2M phase and of keratin 10-positive cells revealed that calcipotriol reduced both indices significantly during treatment of psoriatic plaques. Flow cytometric analysis of epidermal cell suspensions using triple labeling for epidermal proliferation, expression of keratin 10, and vimentin permits a quantitative assessment of DNA synthesis selectively in the basal cells of the epidermis, an estimation of the distribution of the basal and suprabasal compartments, and a quantification of the distribution of mesenchymal and nonmesenchymal cells. Using this approach, the interference of tacalcitol with growth control of basal cells was demonstrated. Remarkably, recompartmentalization of basal and suprabasal cells and mesenchymal and nonmesenchymal cells proved to be inconspicuous during this treatment.

Topics: Calcitriol; Dihydroxycholecalciferols; Epidermis; Flow Cytometry; Humans; Immunohistochemistry; Inflammation; Psoriasis

Psoriasis is a chronic inflammatory disease whereby long-term disease control remains a challenge for the patients. Latest evidence suggests that combined topical treatment with steroids and vitamin D analogue foam (Calcipotriol/Betamethasone) is efficient in long-term management of the disease and reducing the number of relapses. Its effects on cellular inflammation and cytokine production remain to be explored. We set out to examine the effect of topical therapies on cellular infiltrate and cytokine profile in the lesional skin of psoriasis patients. This was a monocentric, double-blind, randomized trial with 30 patients. Patients were treated with the combined Calcipotriol/Betamethasone foam, Betamethasone foam alone, Clobetasol Propionate ointment or placebo. 4 mm skin biopsies from lesional and non-lesional sites were taken before and 4 weeks after treatment. Cellular infiltrate, IFNγ and IL-17 were studied by immunofluorescence. Each patient was their own control. Evolution in skin inflammation was studied in parallel with changes in patient's epidermal thickness and their tPASI clinical score. Lesional skin was characterized by increased epidermal thickness, increased number of IL-17 and IFNγ producing CD8+ T cells, NK cells and neutrophils. All treatment reduced epidermal thickness and improved patients tPASI scores. Only the combined Calcipotriol/Betamethasone foam completely abolished epidermal and dermal influx of CD8+ T cells, reduced number of CD8 + IFNγ+ cells (but not CD8 + IL-17+ cells) and significantly reduced the number of MPO+ neutrophils which were predominantly IL-17+. None of the treatments had effect on NK cells. We have shown the combined topical treatment with Calcipotriol/Betamethasone foam to be effective in reducing cellular influx into lesional skin of psoriasis patients and this effect to be superior to emollient or Betamethasone alone. Its previously described efficacy in the clinic may be attributed to its unique and rapid ability to inhibit both adaptive CD8+ T cell and innate immune neutrophilia influx into the skin, which was not observed for the other treatments.

Topics: Betamethasone; Calcitriol; Emollients; Humans; Inflammation; Interleukin-17; Ointments; Psoriasis

The influence of topical application of MC903, an analogue of 1 alpha,25-dihydroxyvitamin D3, on psoriatic plaques was investigated during a long-term treatment study. The parameters for epidermal growth and for inflammation were assessed on frozen sections using immunohistochemical methods to elucidate their modulations in time and the interrelations between the different cell types involved during treatment with MC903. Biopsies were taken before and after 1, 2, 4 and 12 weeks of treatment. Monoclonal antibodies against the hyperproliferation-associated keratin 16, against cycling nuclei, and against T lymphocytes, B lymphocytes, Langerhans cells and CD14-positive cells were used in combination with a polyclonal antibody against polymorphonuclear leucocyte (PMN)-elastase. The earliest change was a statistically significant decrease in PMN after 1 week of treatment followed by a decline of cycling nuclei after 2 weeks. These changes preceded a decrease of T lymphocytes which occurred after 4 weeks. Keratin 16 content tended to diminish after 4 weeks of treatment. CD14+ cells decreased slightly during the observation period, whereas Langerhans cells tended to increase. No B lymphocytes were found. These results suggest that MC903 influences the number of PMN and epidermal growth rather than the number of T lymphocytes.

Topics: Adult; Aged; Aged, 80 and over; Calcitriol; Cell Division; Epidermis; Humans; Immunoenzyme Techniques; Inflammation; Middle Aged; Neutrophils; Psoriasis

PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γ‒mediated T helper type (Th)1-, IL-4‒mediated Th2-, and IL-17A‒mediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1‒deficient mice than in wild-type or Pd-l2‒deficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2‒deficient mice were more severe than that in wild-type or Pd-l1‒deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity.

Topics: Animals; Antigen Presentation; B7-H1 Antigen; Calcitriol; Cells, Cultured; Cytokines; Dendritic Cells; Dermatitis, Atopic; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Humans; Imiquimod; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Programmed Cell Death 1 Ligand 2 Protein; Psoriasis; Skin; Th1 Cells; Th17 Cells; Th2 Cells

Topics: Calcitriol; Chemokine CCL27; Dermatologic Agents; Humans; Inflammation; Psoriasis

Impaired function of filaggrin (FLG) is a major predisposing factor for atopic dermatitis (AD). Several studies on FLG-deficient (Flg

Topics: Animals; Calcitriol; Dermatitis, Atopic; Dermatologic Agents; Disease Models, Animal; Female; Filaggrin Proteins; Inflammation; Intermediate Filament Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout

Atopic dermatitis (AD) is a complex, often lifelong allergic disease with severe pruritus affecting around 10% of both humans and dogs. To investigate the role of mast cells (MCs) and MC-specific proteases on the immunopathogenesis of AD, a vitamin D

Topics: Animals; Calcitriol; Dermatitis, Atopic; Dermatologic Agents; Ear Diseases; Female; Hypersensitivity; Inflammation; Male; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Serine Endopeptidases

Diminished suppressive capacity of regulatory T cells (Treg) has been demonstrated in blood and in lesional skin of psoriatic patients. Treatment with anti-TNFα restored the number and function of circulating Treg in psoriasis. We aimed to study Treg in the skin of psoriatic patients undergoing topical treatment with calcipotriol-betamethasone dipropionate (CBD) ointment (n = 12) or systemic treatment with anti-TNFα agent adalimumab (n = 10). Skin biopsies were collected from patients with chronic plaque psoriasis who responded to the above-mentioned treatments with a SUM-score improvement of at least 50% (at the end of treatment). Biopsies were processed for immunohistochemistry. As Treg function is associated with a numerical balance between Treg and effector T cells, Foxp3/CD4 ratios were calculated. It appeared that both treatments cause a significant decrease in the presence of Foxp3+ cells. However, in patients that were treated with CBD ointment, we observed lower Foxp3/CD4 ratios after 8 weeks of treatment compared to baseline (t = 0: 0.41 ± 0.08; t = 8: 0.22 ± 0.04, P = 0.033), whereas in patients who were treated with adalimumab we observed an increase of the Foxp3/CD4 ratios after 1.5 and 16 weeks of treatment compared to baseline (t = 0: 0.25 ± 0.04; t = 1.5: 0.32 ± 0.06; t = 16: 0.49 ± 0.10, P = 0.15). Based on Foxp3/CD4 ratios, we can conclude that adalimumab treated skin differs from CBD treated skin with regard to the anti-inflammatory/inflammatory balance. We suggest that, in contrast to CBD ointment, adalimumab favours local Treg function in the skin.

Topics: Adalimumab; Administration, Topical; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Betamethasone; Biopsy; Calcitriol; CD4-Positive T-Lymphocytes; Female; Forkhead Transcription Factors; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Ointments; Psoriasis; Skin; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

Chronic skin inflammation in atopic dermatitis (AD) is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. microRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation.. The aim of this study was to investigate the role of miR-146a in skin inflammation in AD.. RNA and protein expression was analyzed using miRNA and mRNA arrays, RT-quantitative PCR, Western blotting, and immunonohistochemistry. Transfection of miR-146a precursors and inhibitors into human primary keratinocytes, luciferase assays, and MC903-dependent mouse model of AD were used to study miR-146a function.. We show that miR-146a expression is increased in keratinocytes and chronic lesional skin of patients with AD. miR-146a inhibited the expression of numerous proinflammatory factors, including IFN-γ-inducible and AD-associated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-γ, TNF-α, or IL-1β. In a mouse model of AD, miR-146a-deficient mice developed stronger inflammation characterized by increased accumulation of infiltrating cells in the dermis, elevated expression of IFN-γ, CCL5, CCL8, and UBD in the skin, and IFN-γ, IL-1β, and UBD in draining lymph nodes. Both tissue culture and in vivo experiments in mice demonstrated that miR-146a-mediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain-containing protein 10 and IL-1 receptor-associated kinase 1. In addition, human CCL5 was determined as a novel, direct target of miR-146a.. Our data demonstrate that miR-146a controls nuclear factor kappa B-dependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.

Topics: Animals; Calcitriol; Cell Movement; Cells, Cultured; Chronic Disease; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Immunity, Innate; Immunosuppression Therapy; Inflammation; Inflammation Mediators; Keratinocytes; Mice; Mice, Inbred C57BL; MicroRNAs; NF-kappa B; RNA Interference; Signal Transduction; Skin; Up-Regulation

The antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and "alarmins" to amplify inflammation in psoriasis. Th17 cytokines are key players in psoriasis pathogenesis and vitamin D analogs feature anti-psoriatic effects; both of these activities could be mediated through epidermal AMP regulation. We show that supernatants of cultured psoriatic T cells induce and release psoriasin and koebnerisin from keratinocytes and the Th17 cytokines IL-17A, tumor necrosis factor-α, and IL-22 differently regulate psoriasin and koebnerisin reflecting their distinct expression pattern in normal and psoriatic skin. IL-17A is the principal inducer of both S100 and their expression is further amplified by cooperating Th17 cytokines in the micromilieu of psoriatic skin. Increased extracellular psoriasin and koebnerisin also synergize as "alarmins" to prime epidermal keratinocytes for production of immunotropic cytokines that further amplify the inflammatory response. Treatment of psoriatic plaques with the vitamin D analog calcipotriol interferes with the S100-mediated positive feedback loop by suppressing the increased production of psoriasin and koebnerisin in psoriatic skin and their Th17-mediated regulation in epidermal keratinocytes. Thus, targeting the S100-amplification loop could be a beneficial anti-inflammatory approach in psoriasis and other inflammatory skin diseases.

Topics: Antimicrobial Cationic Peptides; Calcitriol; Cells, Cultured; Dermatologic Agents; Humans; Inflammation; Interleukin-17; Interleukin-22; Interleukins; Keratinocytes; Psoriasis; S100 Calcium Binding Protein A7; S100 Proteins; Th17 Cells; Tumor Necrosis Factor-alpha

Low level laser or light treatment on the various clinical condition is getting considerable attention now. However, there has been no report about the clinical effect of low level polarized polychromatic noncoherent light (LPPL) on the inflammatory skin disease. We experienced a case of acrodermatitis continua in a pregnant woman refractory to any conventional treatment including the most potent topical steroid. She was successfully treated with LPPL. LPPL could be a possible treatment modality producing substantial clinical result in inflammatory skin condition without any side-effect.

Topics: Acrodermatitis; Adult; Calcitriol; Female; Humans; Inflammation; Light; Phototherapy; Pregnancy; Pregnancy Complications; Psoriasis; Skin Diseases

Dendritic cells (DC) induce or tolerize T cells, and tolerogenic DCs can promote the development of regulatory T cells (Treg) with suppressive activity. Thus, the possibility of manipulating DCs and enhancing their tolerogenic properties using different pharmacologic or biologic agents could be exploited to control a variety of chronic immuno-mediated inflammatory conditions. Among agents able to promote induction of tolerogenic DCs, vitamin D receptor (VDR) agonists have attracted considerable attention, also because of their potential in clinical translation. DCs are key targets for the immunomodulatory effects of VDR agonists, which shape DC phenotype and function, enhancing their tolerogenicity in adaptive immune responses. Tolerogenic DCs induced by a short treatment with VDR agonists promote CD4+CD25+Foxp3+ Treg cells that are able to mediate transplantation tolerance and to arrest the development of autoimmune diseases. VDR agonists not only favor induction of CD4+CD25+ Treg cells, but can also enhance their recruitment at inflammatory sites. The tolerogenic properties induced by VDR agonists in DCs, leading to enhanced Treg cell development, likely contribute to the beneficial activity of these hormone-like molecules in autoimmune disease and graft rejection models, highlighting their applicability to the treatment of chronic inflammatory conditions sustained by autoreactive or alloreactive immune responses.

Topics: Animals; Antineoplastic Agents; Calcitriol; Cytokines; Dendritic Cells; Dermatologic Agents; Humans; Immune Tolerance; Immunologic Factors; Inflammation; Receptors, Calcitriol; T-Lymphocytes, Regulatory