Genotype-Dependent Effects of TGF-beta 1 on Mast Cell Function: Targeting the Stat5 Pathway

• Type of Material: Article
• Authors: Josephine Fernando, Virginia Commonwealth University; Travis W. Faber, Virginia Commonwealth University; Nicholas A. Pullen, Virginia Commonwealth University; Yves T. Falanga, Virginia Commonwealth University; Elizabeth Motunrayo Kolawole, Virginia Commonwealth University; Carole A. Oskeritzian, Virginia Commonwealth University; Brian O. Barnstein, Virginia Commonwealth University; Geethani Bandara, National Institute of Allergy and Infectious Diseases; Geqiang Li, Harvard University; Lawrence B. Schwartz, Virginia Commonwealth University; Sarah Spiegel, Virginia Commonwealth University; David B. Straus, Virginia Commonwealth University; Daniel H. Conrad, Virginia Commonwealth University; Kevin Bunting, Emory University; John J. Ryan, Virginia Commonwealth University
• Language: English
• Date: 2013-11-01
• Publisher: American Association of Immunologists
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2019 by The American Association of Immunologists, Inc.
• Final Published Version (URL): http://dx.doi.org/10.4049/jimmunol.1202723
• Title of Journal or Parent Work: Journal of Immunology
• ISSN: 0022-1767
• Volume: 191
• Issue: 9
• Start Page: 4505
• End Page: 4513
• Grant/Funding Information: Supported by grants from the National Institutes of Health (1R01AI59638 to JJR, U19AI077435 to JR, SS, and DC; 2R01DK059380 to KDB; K01AR053186 and 1R01AI095494 to CAO).
• Keywords: Immunology; GROWTH-FACTOR-BETA; TRANSCRIPTION 5; SIGNAL TRANSDUCER; T-CELLS; NECROSIS-FACTOR-ALPHA; TGF-BETA; Life Sciences & Biomedicine; CYTOKINE PRODUCTION; IGE; GENE-EXPRESSION; Science & Technology; MOUSE MODEL
• Research Categories: Health Sciences, Immunology; Biology, Genetics

Abstract

We previously demonstrated that TGF-β1 suppresses IgE-mediated signaling in human and mouse mast cells in vitro, an effect that correlated with decreased expression of the high-affinity IgE receptor, FcεRI. The in vivo effects of TGF-β1 and the means by which it suppresses mast cells have been less clear. This study shows that TGF-β1 suppresses FcεRI and c-Kit expression in vivo. By examining changes in cytokine production concurrent with FcεRI expression, we found that TGF-β1 suppresses TNF production independent of FcεRI levels. Rather, IgE-mediated signaling was altered. TGF-β1 significantly reduced expression of Fyn and Stat5, proteins critical for cytokine induction. These changes may partly explain the effects of TGF-β1, because Stat5B overexpression blocked TGF-mediated suppression of IgE-induced cytokine production. We also found that Stat5B is required for mast cell migration toward stem cell factor, and that TGF-β1 reduced this migration. We found evidence that genetic background may alter TGF responses. TGF-β1 greatly reduced mast cell numbers in Th1-prone C57BL/6, but not Th2-prone 129/Sv mice. Furthermore, TGF-β1 did not suppress IgE-induced cytokine release and did increase c-Kit-mediated migration in 129/Sv mast cells. These data correlated with high basal Fyn and Stat5 expression in 129/Sv cells, which was not reduced by TGF-β1 treatment. Finally, primary human mast cell populations also showed variable sensitivity to TGF-β1-mediated changes in Stat5 and IgEmediated IL-6 secretion. We propose that TGF-β1 regulates mast cell homeostasis, and that this feedback suppression may be dependent on genetic context, predisposing some individuals to atopic disease.