期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：12
页码：7241-7246
DOI：10.1073/pnas.0731875100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The multifunctional transforming growth factor {beta} receptor (T{beta}R) ligand pair plays a central role in the regulation of lymphocyte homeostasis and prevention of autoimmunity. Although the mechanisms underlying the induction of transcriptional modulators by T{beta}R have been studied in considerable detail, relatively little is known about the regulatory pathways targeted. To shed light on the mechanisms involved in negative regulation of B cell responses we identified T{beta}R-dependent transcriptome changes by comparative gene expression profiling of normal and T{beta}R-deficient primary B cells. The data reveal T{beta}R-mediated induction of inhibitors of antigen receptor signaling (Ship-1, CD72) as well as inhibitors of the Jak/Stat pathway and signaling by means of Toll-like receptors (SOCS1,3). These inhibitory effects are complemented by induction of antiproliferative transcription factors. In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca2+ flux (inositol trisphosphate receptor subtype 2) are induced by T{beta}R, indicating enhancement of the Ca2+ storage/ release system and chemotactic responses. Suppression of proapoptotic genes suggests support of cell survival. Confirming the shift in B cell responsiveness, antigen-receptor-mediated activation of Syk and phospholipase C-{gamma}2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2+ release, and cell survival are enhanced in transforming growth factor-{beta}-sensitive B cells. The data provide a molecular basis for T{beta}R-mediated inhibition of B cell responsiveness and indicate that T{beta}R maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to microenvironmental cues.
