title: Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice.
abstract: Myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNFR and TLR families, whose signals are transduced by TNFR-associated factor (TRAF) molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I IFN production, but the in vivo function of TRAF3 in myeloid cells remains unknown. In this article, we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3(-/-)) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-κB2 activation. However, in response to injections with LPS (a bacterial mimic) or polyinosinic-polycytidylic acid (a viral mimic), M-TRAF3(-/-) mice exhibited an altered profile of cytokine production. M-TRAF3(-/-) mice immunized with T cell-independent and -dependent Ags displayed elevated T cell-independent IgG3 and T cell-dependent IgG2b responses. Interestingly, 15- to 22-mo-old M-TRAF3(-/-) mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ 08854;
authors.forename: Almin I
authors.initials: AI
authors.lastname: Lalani
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854;
authors.forename: Carissa R
authors.initials: CR
authors.lastname: Moore
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854;
authors.forename: Chang
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854;
authors.forename: Benjamin Z
authors.initials: BZ
authors.lastname: Kreider
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854;
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903 xiep@rci.rutgers.edu.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D009504:Neutrophils / Q000276:immunology*; D011070:Poly I-C; D013601:T-Lymphocytes / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D052003:NF-kappa B p52 Subunit; D048008:TNF Receptor-Associated Factor 3; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011070:Poly I-C