title: Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages.
abstract: Signal transduction from toll-like receptors (TLRs) is important for innate immunity against infections, but deregulated TLR signalling contributes to inflammatory disorders. Here we show that myeloid cell-specific ablation of TRAF2 greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and exacerbates colitis in an animal model of inflammatory bowel disease. TRAF2 deficiency does not enhance upstream signalling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction. Interestingly, TRAF2 controls the fate of c-Rel and IRF5 via a proteasome-dependent mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP. We further show that TRAF2 also regulates inflammatory cytokine production in tumour-associated macrophages and facilitates tumour growth. These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signalling.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Yanchuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Dongdan Santiao 5#, Beijing 100005, China.
authors.forename: Yanpan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Dongdan Santiao 5#, Beijing 100005, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ge
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA [2] Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA [3] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D003092:Colitis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D047992:TNF Receptor-Associated Factor 2; D051193:Toll-Like Receptors