title: IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages.
abstract: Interleukin-10 (IL-10) plays an important role in prevention of chronic inflammation in vivo. However, the molecular mechanism by which IL-10 exerts its anti-inflammatory response is poorly understood. Here, we performed a microarray analysis and identified Bcl-3 as an IL-10-inducible gene in macrophages. Lentiviral vector-mediated expression of Bcl-3 inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNF-alpha), but not IL-6, in macrophages. In Bcl-3-transduced and IL-10-pretreated macrophages, LPS-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) p65 was not impaired. However, DNA binding by NF-kappaB p50/p65 was profoundly inhibited. Nuclear localization of Bcl-3 was associated with inhibition of LPS-induced TNF-alpha production. Overexpression of Bcl-3 suppressed activation of the TNF-alpha promoter, but not the IL-6 promoter. Bcl-3 interacted with NF-kappaB p50 and was recruited to the TNF-alpha promoter, but not the IL-6 promoter, indicating that Bcl-3 facilitates p50-mediated inhibition of TNF-alpha expression. Furthermore, Bcl-3-deficient macrophages showed defective IL-10-mediated suppression of LPS induction of TNF-alpha, but not IL-6. These findings suggest that IL-10-induced Bcl-3 is required for suppression of TNF-alpha production in macrophages.
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kuwata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000081242:B-Cell Lymphoma 3 Protein; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D004247:DNA