Cytosolic antiviral RNA recognition pathway activates caspases 1 and 3

被引:78
作者
Rintahaka, Johanna [1 ]
Wiik, Daniel [2 ]
Kovanen, Panu E. [2 ]
Alenius, Harri [1 ]
Matikainen, Sampsa [1 ]
机构
[1] Univ Helsinki, Finnish Inst Occupat Hlth, Unit Excellence Immunotoxicol, Helsinki 00250, Finland
[2] Univ Helsinki, Haartman Inst, Dept Pathol, Helsinki 00250, Finland
关键词
D O I
10.4049/jimmunol.180.3.1749
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
During an innate immune response, macrophages recognize viruses by their pattern recognition receptors. In this study, we have studied the role of membrane-associated TLRs and cytoplasmic retinoic acid inducible gene-I (RIG-I)-like receptors (RLR) in regulation of IFN-beta, IL-29, IL-1 beta, and IL-18 production and caspases 1 and 3 activation in human macrophages. We provide evidence that TLRs are mainly involved in transcriptional up-regulation of IL-1 beta gene expression, whereas cytosolic dsRNA recognition pathway stimulates powerful IFN-beta and IL-29 gene transcription. However, robust IL-1 beta secretion occurred only if two TLRs were triggered simultaneously or if a single TLR was activated in conjunction with the RLR pathway. Markedly, TLR activation did not stimulate IL-18 processing or secretion. In contrast, triggering of cytosolic RNA recognition pathway with poly(I:C) transfection or influenza A virus infection resulted in caspase-1- and -3-mediated proteolytic processing of pro-IL-18 and secretion of biologically active IL-18. Furthermore, caspase 3-dependent processing of pro-IL-18 was also observed in human HaCaT keratinocytes, and forced expression of RIG-I and its downstream effector, mitochondrial antiviral signaling protein, activated proteolytic processing of pro-IL-18, caspase-3, and apoptosis in these cells. The present results indicate that in addition to robust IFN-beta, IL-29, IL-1 beta, and IL-18 generation, RIG-I/mitochondrial antiviral signaling protein pathway activates caspase-3, suggesting a role for these RIG-I-like receptors beyond the innate cytokine response, hence, in the induction of apoptosis of the virus-infected cell.
引用
收藏
页码:1749 / 1757
页数:9
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