Th17 CYTOKINES INTERLEUKIN (IL)-17 AND IL-22 MODULATE DISTINCT INFLAMMATORY AND KERATINOCYTE-RESPONSE PATHWAYS.

• TR Number: 635
• Authors: Nograles, K.E., Zaba, L.C., Guttman-Yassky, E., Fuentes-Duculan, J., Suarez-Farinas, M., Cardinale, I., Khatcherian, A., Gonzalez,  J., Pierson, K.C., White, T.R., Pensabene, C., Coats, I., Novitskaya, I., Lowes, M.A. and Krueger, J.G.  Laboratory of Investigative Dermatology and Translational Immunomonitoring Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY 10065, U.S.A.
• Materials Tested: IL-17, IL-22

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.