title: A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses.
abstract: The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation.
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Sihan
authors.initials: S
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.|Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.|Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Xinchen
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Weida
authors.initials: W
authors.lastname: Li
authors.affiliation: Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Luan
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C497411:Crem protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051786:Cyclic AMP Response Element Modulator; D048051:p38 Mitogen-Activated Protein Kinases