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Cytosolic Antiviral RNA Recognition Pathway Activates Caspases 1 and 3¹

Johanna Rintahaka^*, Daniel Wiik, Panu E. Kovanen, Harri Alenius^* and Sampsa Matikainen^2,*

^* Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health; and Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland

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-β, IL-29, IL-1β, 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-1β gene expression, whereas cytosolic dsRNA recognition pathway stimulates powerful IFN-β and IL-29 gene transcription. However, robust IL-1β 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-β, IL-29, IL-1β, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Research Council for Biosciences and Environment of the Academy of Finland, and the Sigrid Juselius Foundation.

² Address correspondence and reprint requests to Dr. Sampsa Matikainen, Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, 00250 Helsinki, Finland. E-mail address: sampsa.matikainen{at}ttl.fi

³ Abbreviations used in this paper: PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; DC, dendritic cell; RIG-I, retinoid acid inducible gene-I; RLR, RIG-I-like receptor; MDA-5, melanoma differentiation-associated gene-5; poly(I:C), polyinosic-polycytidylic acid; NALP, NACHT-leucine-rich repeat and pyrin-domain containing protein; NTC, no template control; C_T, cycle threshold value; MAVS, Mitochondrial antiviral signalling protein; t-Poly(I:C), transfected Poly(I:C).