| First Author | Fernando J | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 9 | Pages | 4505-13 |
| PubMed ID | 24068671 | Mgi Jnum | J:206245 |
| Mgi Id | MGI:5548260 | Doi | 10.4049/jimmunol.1202723 |
| Citation | Fernando J, et al. (2013) Genotype-dependent effects of TGF-beta1 on mast cell function: targeting the Stat5 pathway. J Immunol 191(9):4505-13 |
| abstractText | We previously demonstrated that TGF-beta1 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, FcepsilonRI. The in vivo effects of TGF-beta1 and the means by which it suppresses mast cells have been less clear. This study shows that TGF-beta1 suppresses FcepsilonRI and c-Kit expression in vivo. By examining changes in cytokine production concurrent with FcepsilonRI expression, we found that TGF-beta1 suppresses TNF production independent of FcepsilonRI levels. Rather, IgE-mediated signaling was altered. TGF-beta1 significantly reduced expression of Fyn and Stat5, proteins critical for cytokine induction. These changes may partly explain the effects of TGF-beta1, 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-beta1 reduced this migration. We found evidence that genetic background may alter TGF responses. TGF-beta1 greatly reduced mast cell numbers in Th1-prone C57BL/6, but not Th2-prone 129/Sv mice. Furthermore, TGF-beta1 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-beta1 treatment. Finally, primary human mast cell populations also showed variable sensitivity to TGF-beta1-mediated changes in Stat5 and IgE-mediated IL-6 secretion. We propose that TGF-beta1 regulates mast cell homeostasis, and that this feedback suppression may be dependent on genetic context, predisposing some individuals to atopic disease. |
