title: Differential role for p120-catenin in regulation of TLR4 signaling in macrophages.
abstract: Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain-containing adapter-inducing IFN-β-dependent IFN regulatory factor 3 activation and release of IFN-β upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-β signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612;
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612; Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China;
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612; Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China;
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232;
authors.forename: Albert B
authors.initials: AB
authors.lastname: Reynolds
authors.affiliation: Department of Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210; and.
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612; Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612;
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612; Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612 gchu@uic.edu.
authors.forename: Guochang
authors.initials: G
authors.lastname: Hu
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D051177:Catenins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D004705:Endocytosis / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D034622:RNA Interference; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051177:Catenins; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C000722349:Ctnnd1 protein, mouse