Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice.
Chronic liver injury causes liver regeneration, resulting in fibrosis. The proinflammatory cytokine tumor necrosis factor (TNF) is involved in the pathogenesis of many acute and chronic liver diseases. TNF has pleiotropic functions, but its role in liver fibrosis has not been clarified. Chronic repeated injection of CCl4 induces liver fibrosis in mice. We examined whether signaling through TNF receptors was critical for this process, using mice lacking either TNF receptor (TNFR) type 1 or TNFR type 2 to define the pathophysiologic role of TNFR signals in liver fibrosis. Liver fibrosis caused by chronic CCl4 exposure was TNF-dependent; histological fibrosis was seen in wild-type (WT) and TNFR-2 knockout (KO) mice, but not in TNFR-1 KO mice. Furthermore, a marked reduction in procollagen and TGF-beta synthesis was observed in TNFR-1 KO mice, which also had little detectable NF-kappa B, STAT3, and AP1 binding, and reduced levels of liver interleukin-6 (IL-6) mRNA compared to WT and TNFR-2 KO mice. In conclusion, our results indicate the possibility that NF-kappa B, STAT3, and AP1 binding by signals transduced through TNFR-1 plays an important role in liver fibrosis formation.
Sudo
Kaori
K
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. kaorin-s@cc.gifu-u.ac.jp
Yamada
Yasuhiro
Y
Moriwaki
Hisataka
H
Saito
Kuniaki
K
Seishima
Mitsuru
M
D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000494:pharmacology*; D017353:Gene Deletion; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053781:Transforming Growth Factor beta2; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D015850:Interleukin-6; D011347:Procollagen; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002251:Carbon Tetrachloride