Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice.
In autoimmune hepatitis, strong TGF-beta1 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.
Schramm
Christoph
C
First Department of Medicine, Johannes Gutenberg-University, 55101 Mainz, Germany.
Protschka
Martina
M
Köhler
Heinz H
HH
Podlech
Jürgen
J
Reddehase
Matthias J
MJ
Schirmacher
Peter
P
Galle
Peter R
PR
Lohse
Ansgar W
AW
Blessing
Manfred
M
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D015152:Blotting, Northern; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D019693:Hepatitis, Autoimmune / Q000473:pathology / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016212:Transforming Growth Factor beta