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Pivotal role of Smad3 in T cell‐mediated hepatitis
Author(s) -
Kremer Michael,
Perry Ashley W.,
Milton Richard J.,
Wheeler Michael D.,
Hines Ian N.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1137-b
Subject(s) - concanavalin a , apoptosis , hepatitis , cytokine , immunology , liver injury , autoimmune hepatitis , t cell , interleukin 2 , chemistry , medicine , endocrinology , cancer research , in vitro , immune system , biochemistry
Transforming growth factor β promotes hepatocellular apoptosis and suppresses hepatic lymphocyte responses in part through activation of Smad3. The purpose of the current study was to determine the importance of Smad3 signaling in an experimental model of autoimmune hepatitis induced by Concanavalin A (ConA), a process involving T cell activation and hepatocellular apoptosis. C57Bl/6 wild type (wt) or Smad3‐deficient (Smad3 −/− ) mice were injected i.v. with 15mg/kg ConA or vehicle. Nine hours post‐ConA injection, wt mice presented with severe hepatitis measured by liver transaminases in conjunction with significant increases in hepatic T helper 1 (T h 1; interferon gamma) and T h 2 (interleukin 4) cytokine production. Absence of Smad3 significantly blunted hepatocellular injury 9 hours post‐ConA injection despite similar increases in T h 1 and exaggerated T h 2 cytokine production. Furthermore, in vitro T cell activation assays also revealed an imbalanced T h 1:T h 2 cytokine production in Smad3 −/− lymphocytes when compared to wt controls. Finally, Smad3 −/− livers showed significant reductions in hepatocellular apoptosis as assessed by terminal UTP nick end labeling when compared to ConA‐treated wt mice. Together, these studies demonstrate the multifunctional importance of Smad3 signaling in the activation of T lymphocytes and induction of hepatocellular apoptosis in an experimental model of autoimmune hepatitis. This work was supported by NIH grant AA014243.