Dendritic Cells Activated by IFN-γ/STAT1 Express IL-31 Receptor and Release Proinflammatory Mediators Upon IL-31 Treatment

J Immunol. 2012 Jun 1;188(11):5319-26. doi: 10.4049/jimmunol.1101044. Epub 2012 Apr 25.

Abstract

IL-31 is a T cell-derived cytokine that signals via a heterodimeric receptor composed of IL-31Rα and oncostatin M receptor β. Although several studies have aimed to investigate IL-31-mediated effects, the biological functions of this cytokine are currently not well understood. IL-31 expression correlates with the expression of IL-4 and IL-13 and is associated with atopic dermatitis in humans, indicating that IL-31 is involved in Th2-mediated skin inflammation. Because dendritic cells are the main activators of Th cell responses, we posed the question of whether dendritic cells express the IL-31R complex and govern immune responses triggered by IL-31. In the current study, we report that primary human CD1c(+) as well as monocyte-derived dendritic cells significantly upregulate the IL-31Rα receptor chain upon stimulation with IFN-γ. EMSAs, chromatin immunoprecipitation assays, and small interfering RNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-γ-dependent IL-31Rα expression. Subsequent IL-31 stimulation resulted in a dose-dependent release of proinflammatory mediators, including TNF-α, IL-6, CXCL8, CCL2, CCL5, and CCL22. Because these cytokines are crucially involved in skin inflammation, we hypothesize that IL-31-specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Dendritic Cells / pathology
  • Feedback
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation Mediators / metabolism*
  • Inflammation Mediators / physiology
  • Interferon-gamma / physiology*
  • Receptors, Interleukin / biosynthesis*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / physiology
  • STAT1 Transcription Factor / physiology*
  • Skin Diseases / immunology
  • Skin Diseases / metabolism
  • Skin Diseases / pathology

Substances

  • IL31RA protein, human
  • Inflammation Mediators
  • Receptors, Interleukin
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferon-gamma