The double-stranded RNA analogue polyinosinic-polycytidylic acid induces keratinocyte pyroptosis and release of IL-36γ.
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.
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Li-Hua
LH
Lian
Katelynn A
KA
Milora
Katherine K
KK
Manupipatpong
Liselotte E
LE
Jensen
D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005408:Flagellin / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C508586:IL36A protein, human; C508588:IL36B protein, human; C508589:IL36G protein, human; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D012333:RNA, Messenger; D005408:Flagellin; D053148:Caspase 3; D053179:Caspase 7; D020170:Caspase 1; D011070:Poly I-C