title: Cytosolic antiviral RNA recognition pathway activates caspases 1 and 3.
abstract: 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-1beta, 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-1beta gene expression, whereas cytosolic dsRNA recognition pathway stimulates powerful IFN-beta and IL-29 gene transcription. However, robust IL-1beta 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-1beta, 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.
authors.affiliation: Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41a, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rintahaka
authors.forename: Daniel
authors.initials: D
authors.lastname: Wiik
authors.forename: Panu E
authors.initials: PE
authors.lastname: Kovanen
authors.forename: Harri
authors.initials: H
authors.lastname: Alenius
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
mesh_terms: D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000821:virology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D007372:Interferons; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D020170:Caspase 1; D053148:Caspase 3; D016207:Cytokines; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016898:Interferon-alpha; D016899:Interferon-beta; D007372:Interferons; D020382:Interleukin-18; D053583:Interleukin-1beta; D007378:Interleukins; D011070:Poly I-C; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D012367:RNA, Viral; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C452820:RIGI protein, human