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Retinoic acid enhances lactoferrin-induced IgA responses by increasing betaglycan expression

Cellular & Molecular Immunology volume 13, pages 862–870 (2016)Cite this article

Abstract

Lactoferrin (LF) and retinoic acid (RA) are enriched in colostrum, milk, and mucosal tissues. We recently showed that LF-induced IgA class switching through binding to betaglycan (transforming growth factor-beta receptor III, TβRIII) and activation of canonical TGF-β signaling. We investigated the combined effect of LF and RA on the overall IgA response. An increase in IgA production by LF was further augmented by RA. This combination effect was also evident in Ig germ-line α (GLα) transcription and GLα promoter activity, indicating that LF in cooperation with RA increased IgA isotype switching. We subsequently found that RA enhanced TβRIII expression and that this increase contributed to LF-stimulated IgA production. In addition to the IgA response, LF and RA in combination also enhanced the expression of the gut-homing molecules C-C chemokine receptor 9 (CCR9) and α4β7 on B cells. Finally, peroral administration of LF and RA enhanced the frequency of CCR9+IgA+ plasma cells in the lamina propria. Taken together, these results suggest that LF in cooperation with RA can contribute to the establishment of gut IgA responses.

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References

  1. Lamm ME . Interaction of antigens and antibodies at mucosal surfaces. Annu Rev Microbiol 1997; 51: 311–340.

    Article  CAS  PubMed  Google Scholar 

  2. Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC . Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 1994; 152: 3282–3293.

    CAS  PubMed  Google Scholar 

  3. Pabst O, Ohl L, Wendland M, Wurbel MA, Kremmer E, Malissen B et al. Chemokine receptor CCR9 contributes to the localization of plasma cells to the small intestine. J Exp Med 2004; 199: 411–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wagner N, Lohler J, Kunkel EJ, Ley K, Leung E, Krissansen G et al. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature 1996; 382: 366–370.

    Article  CAS  PubMed  Google Scholar 

  5. Stavnezer J . Molecular processes that regulate class switching. Curr Top Microbiol Immunol 2000; 245: 127–168.

    CAS  PubMed  Google Scholar 

  6. Coffman RL, Lebman DA, Shrader B . Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med 1989; 170: 1039–1044.

    Article  CAS  PubMed  Google Scholar 

  7. Kim PH, Kagnoff MF . Transforming growth factor-beta 1 is a costimulator for IgA production. J Immunol 1990; 144: 3411–3416.

    CAS  PubMed  Google Scholar 

  8. Sonoda E, Matsumoto R, Hitoshi Y, Ishii T, Sugimoto M, Araki S et al. Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production. J Exp Med 1989; 170: 1415–1420.

    Article  CAS  PubMed  Google Scholar 

  9. Chambon P . A decade of molecular biology of retinoic acid receptors. FASEB J 1996; 10: 940–954.

    Article  CAS  PubMed  Google Scholar 

  10. Tokuyama Y, Tokuyama H . Retinoids as Ig isotype-switch modulators. The role of retinoids in directing isotype switching to IgA and IgG1 (IgE) in association with IL-4 and IL-5. Cell Immunol 1996; 170: 230–234.

    Article  CAS  PubMed  Google Scholar 

  11. Tokuyama H, Tokuyama Y . Retinoic acid induces the expression of germ-line C alpha transcript mainly by a TGF-beta-independent mechanism. Cell Immunol 1997; 176: 14–21.

    Article  CAS  PubMed  Google Scholar 

  12. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006; 314: 1157–1160.

    Article  CAS  Google Scholar 

  13. Seo GY, Jang YS, Kim HA, Lee MR, Park MH, Park SR et al. Retinoic acid, acting as a highly specific IgA isotype switch factor, cooperates with TGF-β1 to enhance the overall IgA response. J Leukoc Biol 2013; 94: 325–335.

    Article  CAS  PubMed  Google Scholar 

  14. Lonnerdal B . Nutritional roles of lactoferrin. Curr Opin Clin Nutr Metab Care 2009; 12: 293–297.

    Article  CAS  PubMed  Google Scholar 

  15. Legrand D, Elass E, Carpentier M, Mazurier J . Interactions of lactoferrin with cells involved in immune function. Biochem Cell Biol 2006; 84: 282–290.

    Article  CAS  PubMed  Google Scholar 

  16. Puddu P, Valenti P, Gessani S . Immunomodulatory effects of lactoferrin on antigen presenting cells. Biochimie 2009; 91: 11–18.

    Article  CAS  PubMed  Google Scholar 

  17. Bilandzic M, Stenvers KL . Betaglycan: a multifunctional accessory. Mol Cell Endocrinol 2011; 339: 180–189.

    Article  CAS  PubMed  Google Scholar 

  18. López-Casillas F, Wrana JL, Massagué J . Betaglycan presents ligand to the TGF beta signaling receptor. Cell 1993; 73: 1435–1444.

    Article  Google Scholar 

  19. Jang YS, Seo GY, Lee JM, Seo HY, Han HJ, Kim SJ et al. Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-β signaling. Mucosal Immunol 2015; 8: 906–917.

    Article  CAS  PubMed  Google Scholar 

  20. Iigo M, Alexander DB, Long N, Xu J, Fukamachi K, Futakuchi M et al. Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine. Biochimie 2009; 91: 86–101.

    Article  CAS  PubMed  Google Scholar 

  21. Park M-H, Park S-R, Lee M-R, Kim Y-H, Kim P-H . Retinoic acid induces expression of Ig germ line α transcript, an IgA isotype switching indicative, through retinoic acid receptor. Genes Genomics 2011; 33: 83–88.

    Article  CAS  Google Scholar 

  22. Park SR, Lee JH, Kim PH . Smad3 and Smad4 mediate transforming growth factor-beta1-induced IgA expression in murine B lymphocytes. Eur J Immunol 2001; 31: 1706–1715.

    Article  CAS  PubMed  Google Scholar 

  23. Pardali E, Xie XQ, Tsapogas P, Itoh S, Arvanitidis K, Heldin CH et al. Smad and AML proteins synergistically confer transforming growth factor beta1 responsiveness to human germ-line IgA genes. J Biol Chem 2000; 275: 3552–3560.

    Article  CAS  PubMed  Google Scholar 

  24. Kim PH, Kagnoff MF . Transforming growth factor beta 1 increases IgA isotype switching at the clonal level. J Immunol 1990; 145: 3773–3778.

    CAS  PubMed  Google Scholar 

  25. Li SC, Rothman PB, Zhang J, Chan C, Hirsh D, Alt FW . Expression of I mu-C gamma hybrid germline transcripts subsequent to immunoglobulin heavy chain class switching. Int Immunol 1994; 6: 491–497.

    Article  CAS  PubMed  Google Scholar 

  26. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000; 102: 553–563.

    Article  CAS  PubMed  Google Scholar 

  27. Seo GY, Jang YS, Kim J, Choe J, Han HJ, Lee JM et al. Retinoic acid acts as a selective human IgA switch factor. Hum Immunol 2014; 75: 923–929.

    Article  CAS  PubMed  Google Scholar 

  28. Lopez-Casillas F, Riquelme C, Perez-Kato Y, Ponce-Castaneda MV, Osses N, Esparza-Lopez J et al. Betaglycan expression is transcriptionally up-regulated during skeletal muscle differentiation. Cloning of murine betaglycan gene promoter and its modulation by MyoD, retinoic acid, and transforming growth factor-beta. J Biol Chem 2003; 278: 382–390.

    Article  CAS  PubMed  Google Scholar 

  29. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY . Retinoic acid imprints gut-homing specificity on T cells. Immunity 2004; 21: 527–538.

    Article  CAS  PubMed  Google Scholar 

  30. Rivera-Munoz P, Soulas-Sprauel P, Le Guyader G, Abramowski V, Bruneau S, Fischer A et al. Reduced immunoglobulin class switch recombination in the absence of Artemis. Blood 2009; 114: 3601–3609.

    Article  CAS  PubMed  Google Scholar 

  31. Ballard KD, Mah E, Guo Y, Pei R, Volek JS, Bruno RS . Low-fat milk ingestion prevents postprandial hyperglycemia-mediated impairments in vascular endothelial function in obese individuals with metabolic syndrome. J Nutr 2013; 143: 1602–1610.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2010-0012311 to Pyeung-Hyeun Kim and 2013R1A1A2057931 to Goo-Young Seo) and the second stage of the Brain Korea 21 program. Studies were conducted at the Institute of Bioscience and Biotechnology at Kangwon National University.

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Author notes

  1. Jeong-Min Lee, Young-Saeng Jang and Bo-Ra Jin: These authors contributed equally to this work.

  2. P-H Kim, Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea. E-mail: phkim@kangwon.ac.kr

  3. G-Y Seo, Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea. E-mail: gyseo@kangwon.ac.kr

Authors and Affiliations

  1. Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea

    Jeong-Min Lee, Young-Saeng Jang, Bo-Ra Jin, Sun-Jin Kim, Hyeon-Jin Kim, Goo-Young Seo & Pyeung-Hyeun Kim

  2. Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea

    Bo-Eun Kwon & Hyun-Jeong Ko

  3. Department of Systems Immunology, College of Biomedical Science, Kangwon National University, Chuncheon, 200-701, Republic of Korea

    Sung-il Yoon

  4. College of Veterinary Medicine, Kangwon National University, Chuncheon, 200-701, Gangwon, Republic of Korea

    Geun-Shik Lee

  5. Department of Animal Life and Environmental Science, College of Agriculture and Life Science, Hankyong National University, Anseong-si, 456-749, Republic of Korea

    Woan-Sub Kim

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Supplementary information accompanies the paper on Cellular & Molecular Immunology website: http://www.nature.com/cmi.

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Lee, JM., Jang, YS., Jin, BR. et al. Retinoic acid enhances lactoferrin-induced IgA responses by increasing betaglycan expression. Cell Mol Immunol 13, 862–870 (2016). https://doi.org/10.1038/cmi.2015.73

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