IL-17 Induces an Expanded Range of Downstream Genes in Reconstituted Human Epidermis Model

Abstract

BackgroundIL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.Methodology/Principal FindingsGiven the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes.Conclusions/SignificanceThe genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist.

Human Translational Research in Psoriasis Using CLA+ T Cells

“…MCPIP1 activity has been linked to many diferent biological processes within various cell types, such as inhibition of inlammation, angiogenesis, cell migration, or cell diferentiation [56], but no prior evidence of MCPIP1 expression and function in the skin had been reported. In this study, MCPIP1 expression was found to be aberrantly expressed by suprabasal keratinocytes of psoriasis lesions, which is consistent with the distribution of that described for IL-17RA in the psoriatic epidermis [57,58]. In this regard, only diferentiating keratinocytes isolated from psoriatic lesional skin, but not from healthy skin, were susceptible to undergo an increased Human Translational Research in Psoriasis Using CLA+ T Cells http://dx.doi.org/10.5772/67815 67 expression of MCPIP1 to exogenous IL-17A.…”

Isolation of all CD44 transcripts in human epidermis and regulation of their expression by various agents

“…Plasmin has been shown to be involved in wound healing by promoting migration of epidermal keratinocytes coupled with enhanced phagocytic-killing and inhibition of proliferation, which may facilitate re-epithelialization following skin injury [68] and has been shown to play a role in the amplification of psoriasiform skin inflammation in mice [69]. H 2 O 2 has been demonstrated to be involved in wound healing [70], UV-induced DNA damage in keratinocytes [71], and skin blanching [72], IL-17 is a critical component of the Il-17/Il-23 pathway, which is involved skin inflammation and pathogenesis of psoriasis [73][74][75][76]. TGFβ1 has been shown to be involved in control of wound healing and inhibition of keratinocyte proliferation [77].…”

The Caspian Littoral Strip in Azerbaijan is concerned with the State of Ecology of Heavily Exposed Metals

“…However, with the addition of a cytokine cocktail, normal 3Dskin equivalent can adapt a psoriasis-like phenotype and gene expression profile. Previous studies revealed that IL-22 or a mixture of IL-17, IL-22 and TNF-α triggered hyperplasia in normal 3D skin equivalent, with a reduced expression of differentiation-related genes and up regulation of psoriasis markers [12]. Full thickness skin equivalents, which have functional dermal matrix and fibroblasts, are more similar to human skin.…”