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

Abstract

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.

• Authors: Li-Hua Lian, Katelynn A Milora, Katherine K Manupipatpong, Liselotte E Jensen
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 132 Issue 5 Pg. 1346-53 (May 2012) ISSN: 1523-1747 [Electronic] United States
• PMID: 22318382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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