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Am J Physiol Gastrointest Liver Physiol 284: G525-G535, 2003. First published December 4, 2002; doi:10.1152/ajpgi.00286.2002
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Vol. 284, Issue 3, G525-G535, March 2003

Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice

Christoph Schramm1, Martina Protschka2, Heinz H. Köhler3, Jürgen Podlech4, Matthias J. Reddehase4, Peter Schirmacher5, Peter R. Galle1, Ansgar W. Lohse1, and Manfred Blessing2

1 First Department of Medicine, 3 Department of Pathology, 2 First Department of Medicine Pathophysiology Section, and 4 Department of Virology, Johannes Gutenberg-University, 55101 Mainz; and 5 Department of Pathology, University of Cologne, 50931 Cologne, Germany

In autoimmune hepatitis, strong TGF-beta 1 expression is found in the inflamed liver. TGF-beta overexpression may be part of a regulatory immune response attempting to suppress autoreactive T cells. To test this hypothesis, we determined whether impairment of TGF-beta signaling in T cells leads to increased susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of strain FVB/N were generated expressing a dominant-negative TGF-beta type II receptor in T cells under the control of the human CD2 promoter/locus control region. On induction of EAH, transgenic mice showed markedly increased portal and periportal leukocytic infiltrations with hepatocellular necroses compared with wild-type mice (median histological score = 1.8 ± 0.26 vs. 0.75 ± 0.09 in wild-type mice; P < 0.01). Increased IFN-gamma production (118 vs. 45 ng/ml) and less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF-beta signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-beta in immune homeostasis in the liver and may teleologically explain TGF-beta upregulation in response to T cell-mediated liver injury.

transgenic mice; dominant-negative transforming growth factor-beta type II receptor


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