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

2003; American Physiological Society; Volume: 284; Issue: 3 Linguagem: Inglês

10.1152/ajpgi.00286.2002

1522-1547

Christoph Schramm, Martina Protschka, H. Köhler, Jürgen Podlech, Matthias J. Reddehase, Peter Schirmacher, Peter R. Galle, Ansgar W. Lohse, Manfred Blessing,

Pediatric Hepatobiliary Diseases and Treatments

In autoimmune hepatitis, strong TGF-β1 expression is found in the inflamed liver. TGF-β 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-β 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-β 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-γ 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-β signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-β in immune homeostasis in the liver and may teleologically explain TGF-β upregulation in response to T cell-mediated liver injury.