A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
TH1 cytokines have been suggested to contribute to the pathogenesis of T-cell-mediated liver injury and inflammation. However, the molecular signaling pathways involved in such injury are still poorly understood. In the present study, we investigated the role of the STAT1/T-bet signaling pathway in a murine model of T-cell-mediated liver inflammation induced by the application of concanavalin A (Con A) using newly created STAT1 transgenic mice as well as STAT1- and T-bet-deficient mice. Liver injury induced by Con A was associated with an increase of both pSTAT1 and T-bet levels in the liver. Furthermore, functional studies suggested a pathogenic role for STAT1 in Con A-induced liver injury, because transgenic mice overexpressing STAT1 under the control of the CD2 promoter/enhancer construct showed elevated interferon gamma (IFN-gamma) and IRF-1 levels as well as significantly augmented liver injury following administration of Con A. Consistently, we observed that both STAT1-deficient and T-bet-deficient mice were protected from such T-cell-dependent liver injury. In conclusion, these findings suggest a key pathogenic role for the STAT1/T-bet signaling pathway for T-cell activation in the Con A model of T-cell-mediated liver pathology.
Siebler
Jürgen
J
Labor für Klinische Immunologie I, I Medizinische Klinik, Johannes Gutenberg Universität, Mainz, Germany.
Wirtz
Stefan
S
Klein
Sonja
S
Protschka
Martina
M
Blessing
Manfred
M
Galle
Peter R
PR
Neurath
Markus F
MF
D000818:Animals; D003208:Concanavalin A / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D006505:Hepatitis / Q000209:etiology*; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000096:biosynthesis; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D003208:Concanavalin A; D007371:Interferon-gamma