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.

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

Materials Tested

IL-17, IL-22

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