Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways

Br J Dermatol. 2008 Nov;159(5):1092-102. doi: 10.1111/j.1365-2133.2008.08769.x. Epub 2008 Aug 5.

Abstract

Background: Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)-gamma, 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-gamma, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-17 expressed chemokines that were different from those induced by IFN-gamma, 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-17 and IL-22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chronic Disease
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique / methods
  • Humans
  • Immunohistochemistry
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Interleukin-17 / metabolism
  • Interleukin-17 / pharmacology
  • Interleukins / metabolism
  • Interleukins / pharmacology
  • Keratinocytes / immunology*
  • Keratinocytes / ultrastructure
  • Psoriasis / genetics
  • Psoriasis / immunology*
  • Psoriasis / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Tissue Array Analysis

Substances

  • Cytokines
  • Interleukin-17
  • Interleukins
  • Interferon-gamma
  • interleukin-22