The double-stranded RNA analogue polyinosinic-polycytidylic acid induces keratinocyte pyroptosis and release of IL-36γ

J Invest Dermatol. 2012 May;132(5):1346-53. doi: 10.1038/jid.2011.482. Epub 2012 Feb 9.


IL-36 is the common name for the three IL-1 family members IL-36α, IL-36β, and IL-36γ, formerly known as IL-1F6, IL-1F8, and IL-1F9, respectively. IL-36 appears to have pro-inflammatory activities; however, the physiological function of these cytokines remains unknown. Expression of IL-36 by keratinocytes implies its possible involvement in innate immune responses in the skin. We observed that, of the three IL-36 isoforms, human keratinocytes express high levels of IL-36γ. IL-36γ mRNA expression was dramatically induced by the Toll-like receptor ligands polyinosinic-polycytidylic acid (poly(I:C)) and flagellin. Surprisingly, the IL-36γ protein was released by cells treated with poly(I:C), but remained intracellular in cells treated with flagellin only. poly(I:C), but not flagellin, induced cell death and caspase-3/7 activation. Inhibition of caspase-3/7 and caspase-1 blocked extracellular release of IL-36γ from poly(I:C)-treated cells. Furthermore, caspase-1 inhibition prevented poly(I:C)-induced caspase-3/7 activation. Interestingly, transcription of the gene IL36G was dependent on caspase-1, but not caspase-3/7, activation. This demonstrates that the pathways leading to IL36G transcription and caspase-3/7 activation branch after caspase-1. This divergence of the pathways allows the cells to enter a state of de novo protein synthesis before committing to pyroptosis. Overall, our observations suggest that IL-36γ may be an alarmin that signals the cause, e.g., viral infection, of cell death.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Caspase 1 / metabolism
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Death / drug effects
  • Cells, Cultured
  • Flagellin / pharmacology
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism*
  • Interleukin-1alpha / genetics
  • Interleukin-1beta / genetics
  • Keratinocytes / drug effects*
  • Keratinocytes / immunology
  • Keratinocytes / metabolism*
  • Poly I-C / pharmacology*
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Transcription, Genetic


  • IL36A protein, human
  • IL36B protein, human
  • IL36G protein, human
  • Interleukin-1
  • Interleukin-1alpha
  • Interleukin-1beta
  • RNA, Messenger
  • Flagellin
  • Caspase 3
  • Caspase 7
  • Caspase 1
  • Poly I-C