Cutting edge: innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway.
Influenza A virus (IAV) triggers a contagious respiratory disease that produces considerable lethality. Although this lethality is likely due to an excessive host inflammatory response, the negative feedback mechanisms aimed at regulating such a response are unknown. In this study, we investigated the role of the eight "suppressor of cytokine signaling" (SOCS) regulatory proteins in IAV-triggered cytokine expression in human respiratory epithelial cells. SOCS1 to SOCS7, but not cytokine-inducible Src homology 2-containing protein (CIS), are constitutively expressed in these cells and only SOCS1 and SOCS3 expressions are up-regulated upon IAV challenge. Using distinct approaches affecting the expression and/or the function of the IFNalphabeta receptor (IFNAR)1, the viral sensors TLR3 and retinoic acid-inducible gene I (RIG-I) as well as the mitochondrial antiviral signaling protein (MAVS, a RIG-I signaling intermediate), we demonstrated that SOCS1 and SOCS3 up-regulation requires a TLR3-independent, RIG-I/MAVS/IFNAR1-dependent pathway. Importantly, by using vectors overexpressing SOCS1 and SOCS3 we revealed that while both molecules inhibit antiviral responses, they differentially modulate inflammatory signaling pathways.
Pothlichet
Julien
J
Unité Défense Innée et Inflammation, INSERM U874, Institut Pasteur, 25 Rue du Dr. Roux, Paris, France.
Chignard
Michel
M
Si-Tahar
Mustapha
M
D001980:Bronchi / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000502:physiology*; D011971:Receptors, Immunologic; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
C507964:IFNAR1 protein, human; D011971:Receptors, Immunologic; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D053633:Receptor, Interferon alpha-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases