title: Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-β signaling.
abstract: Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-β1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-β receptor III, TβRIII) and in turn induced phosphorylation of TβRI and Smad3 through formation of the TβRIII/TβRII/TβRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Jang
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: G-Y
authors.initials: GY
authors.lastname: Seo
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: J-M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Seo
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: B-R
authors.initials: BR
authors.lastname: Jin
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology, College of Medicine, Konyang University, Daejeon, Republic of Korea.
authors.forename: S-R
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju, Republic of Korea.
authors.forename: K-J
authors.initials: KJ
authors.lastname: Rhee
authors.affiliation: Department of Animal Life and Environmental Science, College of Agriculture and Life Science, Hankyong National University, Anseong-si, Republic of Korea.
authors.forename: W-S
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: P-H
authors.initials: PH
authors.lastname: Kim
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology*; D007781:Lactoferrin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C071736:betaglycan; D007781:Lactoferrin