Interleukin‐17‐ and protease‐activated receptor 2‐mediated production of CXCL1 and CXCL8 modulated by cyclosporine A, vitamin D₃ and glucocorticoids in human keratinocytes

Abstract

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor which mediates a variety of functions in the skin including cutaneous inflammation. SLIGKV-NH(2) , an agonist peptide for PAR2, enhanced the interleukin (IL)-17-induced production of two CXC chemokines, CXCL1 (GRO-α) and CXCL8 (IL-8), in normal human epidermal keratinocytes (NHEK) in a concentration-dependent manner. The enhanced production of those chemokines was suppressed by a PAR2-specific siRNA. The SLIGKV-NH(2) -induced production of both CXCL1 and CXCL8 was markedly reduced by cyclosporine A. The enhanced production of CXCL1 was suppressed by 1α, 24R-dihydroxyvitamin D(3) , an active form of vitamin D(3) , and weakly by glucocorticoids, dexamethasone and clobetasol propionate, whereas production of CXCL8 was not altered by any of those receptor agonists. In psoriatic skin, the thickened upper spinous layer of the epidermis was positive for PAR2 protein and the expression of the IL17A mRNA was increased. These results suggest that the IL-17-induced pro-inflammatory reaction is enhanced by the activation of PAR2 in keratinocytes, and that the effect of PAR2 is differentially modulated by cyclosporine A, the active form of vitamin D(3) and glucocorticoids.

Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology

“…2 However, absolute proof of immune-mediated pathogenesis is not possible since CsA has some direct effects on keratinocytes. 50,51 Future studies with specific immune antagonists are needed to determine the contribution of specific cytokines to the pathologic epidermal phenotype. We are now experiencing an exciting new era in AD, with narrow-targeted therapeutics entering clinical trials.…”

TWEAK/Fn14 activation induces keratinocyte proliferation under psoriatic inflammation

“…Our results confirmed such Th1/Th17 cytokine profile in psoriatic sera, which is also consistent with the previous report . These cytokines regulate the expression of membrane receptors in keratinocytes , which may consequently alter the reaction of keratinocytes to stimuli signals. The enhancement effect of TWEAK on cell proliferation is seen at the combination with psoriatic cytokines (M5).…”

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

“…(1,25(OH)2D3) exerts immunomodulatory effects on T cells from patients with SR asthma patients, enhancing the impaired steroid-induced IL-10 response in these individuals (31), while others have highlighted the capacity of this molecule to inhibit Th17 responses (32)(33)(34)(35).…”