title: Batf2/Irf1 induces inflammatory responses in classically activated macrophages, lipopolysaccharides, and mycobacterial infection.
abstract: Basic leucine zipper transcription factor Batf2 is poorly described, whereas Batf and Batf3 have been shown to play essential roles in dendritic cell, T cell, and B cell development and regulation. Batf2 was drastically induced in IFN-γ-activated classical macrophages (M1) compared with unstimulated or IL-4-activated alternative macrophages (M2). Batf2 knockdown experiments from IFN-γ-activated macrophages and subsequent expression profiling demonstrated important roles for regulation of immune responses, inducing inflammatory and host-protective genes Tnf, Ccl5, and Nos2. Mycobacterium tuberculosis (Beijing strain HN878)-infected macrophages further induced Batf2 and augmented host-protective Batf2-dependent genes, particularly in M1, whose mechanism was suggested to be mediated through both TLR2 and TLR4 by LPS and heat-killed HN878 (HKTB) stimulation experiments. Irf1 binding motif was enriched in the promoters of Batf2-regulated genes. Coimmunoprecipitation study demonstrated Batf2 association with Irf1. Furthermore, Irf1 knockdown showed downregulation of IFN-γ- or LPS/HKTB-activated host-protective genes Tnf, Ccl5, Il12b, and Nos2. Conclusively, Batf2 is an activation marker gene for M1 involved in gene regulation of IFN-γ-activated classical macrophages, as well as LPS/HKTB-induced macrophage stimulation, possibly by Batf2/Irf1 gene induction. Taken together, these results underline the role of Batf2/Irf1 in inducing inflammatory responses in M. tuberculosis infection.
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Sugata
authors.initials: S
authors.lastname: Roy
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, Health Science Faculty, University of Cape Town, Cape Town 7925, South Africa;
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, Health Science Faculty, University of Cape Town, Cape Town 7925, South Africa;
authors.forename: Suraj P
authors.initials: SP
authors.lastname: Parihar
authors.affiliation: Institute of Natural and Mathematical Sciences, Massey University, North Shore City 0745, New Zealand; and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmeier
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Bogumil
authors.initials: B
authors.lastname: Kaczkowski
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Jay W
authors.initials: JW
authors.lastname: Shin
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, Health Science Faculty, University of Cape Town, Cape Town 7925, South Africa;
authors.forename: Mumin
authors.initials: M
authors.lastname: Ozturk
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, Health Science Faculty, University of Cape Town, Cape Town 7925, South Africa;
authors.forename: Ramona
authors.initials: R
authors.lastname: Hurdayal
authors.affiliation: RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Atsutaka
authors.initials: A
authors.lastname: Kubosaki
authors.affiliation: RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan;
authors.forename: Michiel J L
authors.initials: MJ
authors.lastname: de Hoon
authors.affiliation: RIKEN Omics Science Center, Yokohama 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama 230-0045, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, Health Science Faculty, University of Cape Town, Cape Town 7925, South Africa; harukazu@gsc.riken.jp frank.brombacher@icgeb.org.
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; RIKEN Omics Science Center, Yokohama 230-0045, Japan; harukazu@gsc.riken.jp frank.brombacher@icgeb.org.
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009161:Mycobacterium / Q000276:immunology*; D009164:Mycobacterium Infections / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C576672:BATF2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II