1. Lactoferrin Potentiates Inducible Regulatory T Cell Differentiation through TGF-β Receptor III Binding and Activation of Membrane-Bound TGF-β.
- Author
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Jang YS, Song HE, Seo GY, Jo HJ, Park S, Park HW, Kim TG, Kang SG, Yoon SI, Ko HJ, Lee GS, Park SR, and Kim PH
- Subjects
- Animals, Cell Differentiation drug effects, Cell Differentiation immunology, Colitis immunology, Colitis metabolism, Lactoferrin pharmacology, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Mice, Inbred BALB C, Receptors, Transforming Growth Factor beta drug effects, Receptors, Transforming Growth Factor beta metabolism, Signal Transduction drug effects, Signal Transduction immunology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory metabolism, Transforming Growth Factor beta drug effects, Transforming Growth Factor beta metabolism, Mice, Lactoferrin metabolism, Receptors, Transforming Growth Factor beta immunology, T-Lymphocytes, Regulatory immunology, Transforming Growth Factor beta immunology
- Abstract
Lactoferrin (LF) is known to possess anti-inflammatory activity, although its mechanisms of action are not well-understood. The present study asked whether LF affects the commitment of inducible regulatory T cells (Tregs). LF substantially promoted Foxp3 expression by mouse activated CD4
+ T cells, and this activity was further enhanced by TGF-β1. Interestingly, blocking TGF-β with anti-TGF-β Ab completely abolished LF-induced Foxp3 expression. However, no significant amount of soluble TGF-β was released by LF-stimulated T cells, suggesting that membrane TGF-β (mTGF-β) is associated. Subsequently, it was found that LF binds to TGF-β receptor III, which induces reactive oxygen species production and diminishes the expression of mTGF-β-bound latency-associated peptide, leading to the activation of mTGF-β. It was followed by phosphorylation of Smad3 and enhanced Foxp3 expression. These results suggest that LF induces Foxp3+ Tregs through TGF-β receptor III/reactive oxygen species-mediated mTGF-β activation, triggering canonical Smad3-dependent signaling. Finally, we found that the suppressive activity of LF-induced Tregs is facilitated mainly by CD39/CD73-induced adenosine generation and that this suppressor activity alleviates inflammatory bowel disease., (Copyright © 2021 by The American Association of Immunologists, Inc.)- Published
- 2021
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