title: Suppressors of cytokine signaling 3 is essential for FcγR-mediated inflammatory response via enhancing CCAAT/enhancer-binding protein δ transcriptional activity in macrophages.
abstract: Compelling evidence indicates that suppressor of cytokine signaling 3 (SOCS3) plays a pivotal regulatory role in inflammation. However, the function of SOCS3 in inflammatory responses mediated by Fcγ receptor (FcγR) remains largely unknown. In the current study, we found that SOCS3 expression was greatly enhanced in peritoneal macrophages treated with IgG immune complex (IgG IC). By over-expressing SOCS3 in macrophages, we observed that SOCS3 promoted IgG immune complex-induced production of inflammatory mediators, including IL-6, TNF-α, MIP-2, and MIP-1α. In contrast, SOCS3-defective peritoneal macrophages generated less inflammatory cytokines and chemokines when compared with their wild type counterparts during IgG IC-induced inflammatory responses. We further demonstrated that CCAAT/enhancer-binding protein (C/EBP) δ transcription factor was the major downstream target of SOCS3 in macrophages. These data suggested that SOCS3 was an inflammatory enhancer in IgG IC-treated macrophages by increasing C/EBPδ activity. To elucidate the role for myeloid-derived SOCS3 in IgG IC-induced inflammation in vivo, LysM-cre SOCS3(fl/fl) mice lacking SOCS3 in macrophages and neutrophils were generated. We found that SOCS3 deficiency greatly alleviated IgG IC-induced generation of pro-inflammatory mediators in lungs, consistent with the in vitro data. Our current findings may provide a new theoretical basis for designing drugs for treatment of IgG IC-associated diseases.
authors.affiliation: Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing 210009, China; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative & Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address: ycgagcy@163.com.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Yan
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative & Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Surgery, Tianjin Nankai Hospital, 6 Changjiang Road, Nankai District, Tianjin 300100, China.
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative & Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Surgery, Tianjin Nankai Hospital, 6 Changjiang Road, Nankai District, Tianjin 300100, China. Electronic address: wangximo@126.com.
authors.forename: Ximo
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D018836:Inflammation Mediators; D017452:Receptors, IgG; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta
keywords: C/EBPδ; IgG IC; Peritoneal macrophage; SOCS3