Th17 CYTOKINES INTERLEUKIN (IL)-17 AND IL-22 MODULATE DISTINCT INFLAMMATORY AND KERATINOCYTE-RESPONSE PATHWAYS.
Background Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution. of interferon (IFN)-γ, interleukin (IL)-17 and IL-22 on disease pathogenesis is still unknown. Objectives: In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors. Methods: We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine-treated keratinocytes was performed using moderated paired t-test controlling for false discovery rate using the Benjamini-Hochberg procedure. Results: We demonstrate that T -helper cells producing IL-17, IL-22 and/or IFN-γ, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-l 7 expressed chemokines that were different from those induced by IFN-γ, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL- 22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model. Conclusions: Our results suggest that the Th17 cytokines IL-I7 and IL- 22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.
Acanthosis, CCL20, CXCL8, EFT-400, Full-thickness human skin models, Inflammatory skin disease, Parakeratosis, Psoriasis, S100A7, S100A7 psoriasin, Th 17 cells, Th 17 cytokines, β-defensin
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