title: β-Arrestin 2 negatively regulates Toll-like receptor 4 (TLR4)-triggered inflammatory signaling via targeting p38 MAPK and interleukin 10.
abstract: The control of IL-10 production in Toll-like receptor (TLR) signals remains to be elucidated. Here, we report that β-arrestin 2 positively regulates TLR-triggered IL-10 production in a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism. In vitro studies with cells including peritoneal macrophages and HEK293/TLR4 cells have demonstrated that β-arrestin 2 forms complexes with p38 and facilitates p38 activation after lipopolysaccharide (LPS) stimulation. Deficiency of β-arrestin 2 and inhibition of p38 MAPK activity both ameliorate TLR4-stimulated IL-10 response. Additionally, in vivo experiments show that mice lacking β-arrestin 2 produce less amount of IL-10, and are more susceptible to LPS-induced septic shock which is further enhanced by blocking IL-10 signal. These results reveal a novel mechanism by which β-arrestin 2 negatively regulates TLR4-mediated inflammatory reactions.
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614,; Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China, and.
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Gene D
authors.initials: GD
authors.lastname: LeSage
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Yi
authors.initials: Y
authors.lastname: Caudle
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Charles
authors.initials: C
authors.lastname: Stuart
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China, and. Electronic address: zhongmin_liu@sina.com.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614,. Electronic address: yin@etsu.edu.
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cell Signaling; Endotoxic Shock; IL-10; Inflammation; Protein Kinase; Toll-like Receptor (TLR); p38; β-Arrestin 2