Genotype-dependent effects of TGF-β1 on mast cell function: targeting the Stat5 pathway.
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.
Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
Josephine
J
Fernando
Travis W
TW
Faber
Nicholas A
NA
Pullen
Yves T
YT
Falanga
Elizabeth Motunrayo
EM
Kolawole
Carole A
CA
Oskeritzian
Brian O
BO
Barnstein
Geethani
G
Bandara
Geqiang
G
Li
Lawrence B
LB
Schwartz
Sarah
S
Spiegel
David B
DB
Straus
Daniel H
DH
Conrad
Kevin D
KD
Bunting
John J
JJ
Ryan
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017455:Receptors, IgE / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000096:biosynthesis
D016207:Cytokines; C475664:FCER1A protein, human; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors; D007073:Immunoglobulin E; D019009:Proto-Oncogene Proteins c-kit; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn