Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2

• Published in: Blood Vol. 117; no. 20; pp. 5438 - 5448
• Main Authors: Watanabe-Matsui, Miki, Muto, Akihiko, Matsui, Toshitaka, Itoh-Nakadai, Ari, Nakajima, Osamu, Murayama, Kazutaka, Yamamoto, Masayuki, Ikeda-Saito, Masao, Igarashi, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 19.05.2011; Americain Society of Hematology
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Base Sequence; Basic-Leucine Zipper Transcription Factors - deficiency; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biological and medical sciences; Cell Differentiation; Cells, Cultured; DNA - genetics; DNA - metabolism; DNA Primers - genetics; Gene Expression; Hematologic and hematopoietic diseases; Heme - metabolism; Heme - pharmacology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Immunoglobulin Class Switching; Immunoglobulin G - metabolism; Immunoglobulin M - biosynthesis; Ligands; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Positive Regulatory Domain I-Binding Factor 1; Protein Binding; Protein Stability; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Hematology; Enzyme; Antibody; Ligand; Isotype switch; Heme; Heat shock protein; Heme oxygenase (decyclizing); B-Lymphocyte; Oxidoreductases; Cell differentiation
• DOI: 10.1182/blood-2010-07-296483
• ISSN: 0006-4971

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.