title: TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury.
abstract: TNFα-stimulated gene-6 (TSG6), a 30-kDa protein generated by activated macrophages, modulates inflammation; however, its mechanism of action and role in the activation of macrophages are not fully understood. Here we observed markedly augmented LPS-induced inflammatory lung injury and mortality in TSG6-/-mice compared with WT (TSG6+/+) mice. Treatment of mice with intratracheal instillation of TSG6 prevented LPS-induced lung injury and neutrophil sequestration, and increased survival in mice. We found that TSG6 inhibited the association of TLR4 with MyD88, thereby suppressing NF-κB activation. TSG6 also prevented the expression of proinflammatory proteins (iNOS, IL-6, TNFα, IL-1β, and CXCL1) while increasing the expression of anti-inflammatory proteins (CD206, Chi3l3, IL-4, and IL-10) in macrophages. This shift was associated with suppressed activation of proinflammatory transcription factors STAT1 and STAT3. In addition, we observed that LPS itself up-regulated the expression of TSG6 in TSG6+/+mice, suggesting an autocrine role for TSG6 in transitioning macrophages. Thus, TSG6 functions by converting macrophages from a proinflammatory to an anti-inflammatory phenotype secondary to suppression of TLR4/NF-κB signaling and STAT1 and STAT3 activation.
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Manish
authors.initials: M
authors.lastname: Mittal
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Chinnaswamy
authors.initials: C
authors.lastname: Tiruppathi
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Saroj
authors.initials: S
authors.lastname: Nepal
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Grzych
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Soni
authors.affiliation: Institute for Regenerative Medicine, Texas A&M University Health Science Center and College of Medicine, Bryan, TX 77807 abmalik@uic.edu Prockop@medicine.tamhsc.edu.
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612 abmalik@uic.edu Prockop@medicine.tamhsc.edu.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D065150:Cellular Reprogramming / Q000276:immunology; D007249:Inflammation / Q000517:prevention & control; D018836:Inflammation Mediators / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D055370:Lung Injury / Q000517:prevention & control*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C493487:Tlr4 protein, mouse; C513057:Tnfaip6 protein, mouse; D051197:Toll-Like Receptor 4
keywords: acute lung injury; biological sciences; immunology; inflammation; medical sciences