Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis

J Invest Dermatol. 2011 Dec;131(12):2428-37. doi: 10.1038/jid.2011.234. Epub 2011 Sep 1.


Accumulating evidence indicates that IL-1 family members and Th17 cytokines have a pathogenic role in psoriasis. We investigated the regulatory interactions of the IL-1-like IL-36 cytokine family and the Th17 cytokines in the context of skin inflammation. We observed increased gene expression of all three IL-36 cytokines in a Th17-dominant psoriasis-like animal model. The induction was downregulated by neutralizing IL-22. Expression of the IL-36s was also induced in cultured primary human keratinocytes (KC) by IL-17A and tumor necrosis factor (TNF)-α, and IL-22 synergized with IL-17A and TNF-α. Furthermore, the IL-36s directly induced their own expression and the production of proinflammatory mediators (TNF-α, IL-6, IL-8) in KC. These functions were markedly enhanced with the addition of IL-17A or TNF-α to the cultures. Similarly, IL-36α and IL-36β augmented IL-17A-mediated induction of antibacterial peptides. Finally, we show that the increased gene expression of IL-36 correlated with Th17 cytokines in the lesions of psoriatic patients. Our results indicate that the IL-36 cytokines are not only regulated by Th17 cytokines, but that they themselves can regulate the expression and enhance the function of Th17 cytokines. We propose that a feedback loop between the IL-36 and Th17 cytokines is involved in driving cytokine expression in psoriatic tissues.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / immunology*
  • Female
  • Gene Expression
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / immunology*
  • Keratinocytes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Psoriasis / genetics
  • Psoriasis / immunology*
  • Th17 Cells / immunology*


  • Cytokines
  • IL-1F8 protein, mouse
  • IL1F9 protein, mouse
  • IL36A protein, human
  • IL36B protein, human
  • IL36G protein, human
  • Interleukin-1
  • interleukin 1F6, mouse