title: Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation.
abstract: Nuclear translocation of cytosolic CLIC4 is an essential feature of its proapoptotic and prodifferentiation functions. Here we demonstrate that CLIC4 is induced concurrently with inducible nitric oxide synthase (iNOS) and S-nitrosylated in proinflammatory peritoneal macrophages. Chemical inhibition or genetic ablation of iNOS inhibits S-nitrosylation and nuclear translocation of CLIC4. In macrophages, iNOS-induced nuclear CLIC4 coincides with the pro- to anti-inflammatory transition of the cells because IL-1β and CXCL1 mRNA remain elevated in CLIC4 and iNOS knockout macrophages at late time points, whereas TNFα mRNA is elevated only in the iNOS knockout macrophages. Active IL-1β remains elevated in CLIC4 knockout macrophages and in macrophages in which CLIC4 nuclear translocation is prevented by the NOS inhibitor l-NAME. Moreover, overexpression of nuclear-targeted CLIC4 down-regulates IL-1β in stimulated macrophages. In mice, genetically null for CLIC4, the number of phagocytosing macrophages stimulated by LPS is reduced. Thus, iNOS-induced nuclear CLIC4 is an essential part of the macrophage deactivation program.
authors.affiliation: Laboratory of Cancer Biology and Genetics and Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Malik
authors.forename: Kasey
authors.initials: K
authors.lastname: Jividen
authors.forename: V C
authors.initials: VC
authors.lastname: Padmakumar
authors.forename: Christophe
authors.initials: C
authors.lastname: Cataisson
authors.forename: Luowei
authors.initials: L
authors.lastname: Li
authors.forename: Jessica
authors.initials: J
authors.lastname: Lee
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C479423:CLIC protein, mouse; D018118:Chloride Channels; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse