title: Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2.
abstract: Heme binds to proteins to modulate their function, thereby functioning as a signaling molecule in a variety of biologic events. We found that heme bound to Bach2, a transcription factor essential for humoral immunity, including antibody class switch. Heme inhibited the DNA binding activity of Bach2 in vitro and reduced its half-life in B cells. When added to B-cell primary cultures, heme enhanced the transcription of Blimp-1, the master regulator of plasma cells, and skewed plasma cell differentiation toward the IgM isotype, decreasing the IgG levels in vitro. Intraperitoneal injection of heme in mice inhibited the production of antigen-specific IgM when heme was administered simultaneously with the antigen but not when it was administered after antigen exposure, suggesting that heme also modulates the early phase of B-cell responses to antigen. Heme oxygenase-1, which is known to be regulated by heme, was repressed by both Bach2 and Bach1 in B cells. Furthermore, the expression of genes for heme uptake changed in response to B-cell activation and heme administration. Our results reveal a new function for heme as a ligand of Bach2 and as a modulatory signal involved in plasma cell differentiation.
authors: Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, Japan.
authors: Miki
authors: M
authors: Watanabe-Matsui
authors: Akihiko
authors: A
authors: Muto
authors: Toshitaka
authors: T
authors: Matsui
authors: Ari
authors: A
authors: Itoh-Nakadai
authors: Osamu
authors: O
authors: Nakajima
authors: Kazutaka
authors: K
authors: Murayama
authors: Masayuki
authors: M
authors: Yamamoto
authors: Masao
authors: M
authors: Ikeda-Saito
authors: Kazuhiko
authors: K
authors: Igarashi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006418:Heme / Q000378:metabolism* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000096:biosynthesis; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011485:Protein Binding; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C486316:Bach1 protein, mouse; C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008024:Ligands; D008565:Membrane Proteins; C513258:Prdm1 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D006418:Heme; D004247:DNA; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000074462:Positive Regulatory Domain I-Binding Factor 1