title: Immune complex/Ig negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gamma RIIb-dependent PGE2 production.
abstract: Excessive activation of TLR may induce endotoxin shock and inflammatory diseases, so the negative regulation of TLR-triggered inflammatory response attracts much attention. Nonpathogenic immune complex (IC) and Ig (IC/Ig) have been shown to play important roles in the regulation of immune responses and to be therapeutic in some kinds of autoimmune diseases. However, the role of IC/Ig in the regulation of TLR-triggered inflammatory responses and the underlying mechanisms remain to be fully understood. In this study we demonstrate that IC/Ig can significantly inhibit LPS-induced secretion of TNF-alpha and IL-6 from macrophages by preferentially inducing PGE(2). Pretreatment of mice with IC can protect wild-type mice, but not Fc gammaRIIb(-/-) mice, from lethal endotoxin shock, and significantly reduce the levels of serum TNF-alpha and IL-6 in wild-type mice but not in Fc gammaR IIb(-/-) mice. Furthermore, blockade of PGE(2) by celecoxib restores LPS-induced production of TNF-alpha and IL-6 in the presence of IC both in vitro and in vivo. Accordingly, blockade of PGE(2) production in vivo results in the increased sensitivity of IC-pretreated mice to lethal endotoxin shock. Therefore, IC/Ig can negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gammaRIIb-dependent PGE(2). In addition, our results suggest that down-regulation of NF-kappaB activation and TLR4 expression but activation of protein kinase A pathway in macrophages by IC/Ig contribute to the negative regulatory process. Thus we provide new manner for the immune regulation and mechanistic explanation for nonpathogenic IC/Ig in the treatment of inflammatory or autoimmune diseases.
authors.affiliation: Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, Peoples Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuxun
authors.initials: S
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Yu
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000502:physiology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000936:Antigen-Antibody Complex; D016207:Cytokines; C080571:Fc gamma receptor IIB; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017452:Receptors, IgG; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone