title: Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1.
abstract: The respiratory epithelium consists of lung sentinel cells, which are the first to contact inhaled inflammatory insults, including air pollutants, smoke, and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation resolution is now known to be an active process involving a new genus of lipid mediators, called "specialized proresolving lipid mediators," that includes resolvin D1 (RvD1). We and others have reported that RvD1 counteracts proinflammatory signaling and promotes resolution. A knowledge gap is that the specific cellular targets and mechanisms of action for RvD1 remain largely unknown. In this article, we identified the mechanism whereby RvD1 disrupts inflammatory mediator production induced by the viral mimic polyinosinic-polycytidylic acid [poly(I:C)] in primary human lung epithelial cells. RvD1 strongly suppressed the viral mimic poly(I:C)-induced IL-6 and IL-8 production and proinflammatory signaling involving MAPKs and NF-κB. Most importantly, we found that RvD1 inhibited the phosphorylation of TAK1 (TGF-β-activated kinase 1), a key upstream regulatory kinase common to both the MAPK and NF-κB pathways, by inhibiting the formation of a poly(I:C)-induced signaling complex composed of TAK1, TAB1 (TAK1 binding protein), and TRAF6 (TNF receptor-associated factor 6). We confirmed that ALX/FPR2 and GPR32, two RvD1 receptors, were expressed on human small airway epithelial cells. Furthermore, blocking these receptors abrogated the inhibitory action of RvD1. In this article, we present the idea that RvD1 has the potential to be used as an anti-inflammatory and proresolving agent, possibly in the context of exuberant host responses to damaging respirable agents such as viruses.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642;
authors.forename: Hsi-Min
authors.initials: HM
authors.lastname: Hsiao
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Levy
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fulton
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Owens
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 Patricia_Sime@urmc.rochester.edu.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004281:Docosahexaenoic Acids; D015850:Interleukin-6; D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011070:Poly I-C; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D048029:TNF Receptor-Associated Factor 6; D000099151:MAP Kinase Kinase Kinase 7; C114479:GPR32 protein, human; C442142:HSH2D protein, human; C508600:IL6 protein, human; C486300:TAB1 protein, human; C518399:resolvin D1