title: Calcineurin B stimulates cytokine production through a CD14-independent Toll-like receptor 4 pathway.
abstract: The calcineurin B subunit (CnB) is the regulatory subunit of Cn, a Ca(2+)/calmodulin-dependent serine/threonine protein phosphatase. In this study, we demonstrate that extracellular CnB was effectively internalized through a CD14-independent Toll-like receptor 4 (TLR4) pathway, which led to the phosphorylation of nuclear factor (NF)-kappa-B inhibitor alpha (IκB-α) and upregulation of pro-inflammatory cytokines in human monocytes. CnB-induced IκB-α phosphorylation is completely dependent on TNF receptor-associated factor 3 (TRAF3) but not TRAF6, which is indispensable for IκB-α phosphorylation in response to lipopolysaccharide. The loss-of-function CnB mutants were able to induce IκB-α phosphorylation, further indicating that this novel role of CnB is completely independent of the phosphatase function of Cn. Taken together, these findings demonstrate that CnB is a novel host-derived immunostimulatory factor, having a role as an agonist in monocytes, and specificity in TLR4 signaling through TRAF3 and TRAF6, in response to various agonists.
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Geng
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Jinju
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.|Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
mesh_terms: D019703:Calcineurin / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D004705:Endocytosis; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051550:I-kappa B Kinase; D019703:Calcineurin