Genotype-dependent effects of TGF-β1 on mast cell function: targeting the Stat5 pathway

• Published in: The Journal of immunology (1950) Vol. 191; no. 9; pp. 4505 - 4513
• Main Authors: Fernando, Josephine, Faber, Travis W, Pullen, Nicholas A, Falanga, Yves T, Kolawole, Elizabeth Motunrayo, Oskeritzian, Carole A, Barnstein, Brian O, Bandara, Geethani, Li, Geqiang, Schwartz, Lawrence B, Spiegel, Sarah, Straus, David B, Conrad, Daniel H, Bunting, Kevin D, Ryan, John J
• Format: Journal Article
• Language: English
• Published: United States 01-11-2013
• Subjects: Animals; Cell Movement - immunology; Cells, Cultured; Cytokines - metabolism; Cytokines - secretion; Humans; Immunoglobulin E - immunology; Immunoglobulin E - metabolism; Mast Cells - immunology; Mast Cells - metabolism; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-fyn - metabolism; Proto-Oncogene Proteins c-kit - metabolism; Receptors, IgE - biosynthesis; Receptors, IgE - immunology; Receptors, IgE - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction - immunology; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - immunology; STAT5 Transcription Factor - metabolism; Transforming Growth Factor beta1 - immunology; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factors - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202723

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 IgE-mediated 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.