title: Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression.
abstract: Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11b(hi) regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam(-/-)) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production. CD11b inhibited nuclear factor-kappa B (NF-κB) while promoted activator protein 1 (AP-1) activation through activating sarcoma oncogene (Src), leading to decreased TNF-α while increased IL-10 production. Src interacted with and promoted c-casitas B lineage lymphoma proto-oncogene (c-Cbl)-mediated degradation of the inhibitory subunit p85 of phosphatidylinositol 3-kinase (PI3K). Importantly, Src inhibitor dasatinib aggravated DSS-induced colitis by decreasing IL-10 while increasing TNF-α in vivo. Therefore, CD11b promotes IL-10 production by activating Src-Akt signal pathway. An axis of CD11b-Src pathway is important in balancing homeostasis of TLR-induced pro-inflammatory and anti-inflammatory responses.
authors.affiliation: National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hu
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Han
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Kewei
authors.initials: K
authors.lastname: Qin
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Tianliang
authors.initials: T
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.|National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics*; D016264:Dextran Sulfate; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D039481:CD11b Antigen; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt