Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis.
TNF-alpha has pleiotropic functions, but its role in liver fibrosis has not yet been clarified. To understand the pathophysiologic role of the TNF-alpha/TNF receptor (TNFR) p55 signals in liver fibrosis, 10 mg/kg of dimethylnitrosamine, a specific hepatotoxicant, was administered twice a week into the peritoneal cavity of both TNFRp55 knock-out (KO) and wild-type mice, and the severity of fibrosis was monitored histologically and biochemically. In wild-type mice, histologic analysis demonstrated evident fibrotic changes 1 week after the initiation of dimethylnitrosamine administration, consistent with increased liver collagen contents. Concomitantly, the numbers of Kupffer cells and activated hepatic stellate cells (HSCs) were increased in liver tissue. On the contrary, fibrotic changes were attenuated and the numbers of Kupffer cells and HSCs were decreased in TNFRp55-KO mice. Moreover, gene expression of TNF-alpha and monocyte chemoattractant protein-1, which are involved in Kupffer cell activation or migration, was decreased in the liver of TNFRp55-KO mice. Collectively, TNFRp55-mediated signals may regulate activation of Kupffer cells and HSCs and eventually enhance fibrotic process.
Kitamura
Kazuya
K
Department of Gastroenterology, Graduate School of Medicinal Sciences, Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Nakamoto
Yasunari
Y
Akiyama
Mariko
M
Fujii
Chifumi
C
Kondo
Toshikazu
T
Kobayashi
Kenichi
K
Kaneko
Shuichi
S
Mukaida
Naofumi
N
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004128:Dimethylnitrosamine / Q000633:toxicity; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D018932:Chemokine CCL2; D017931:DNA Primers; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D020782:Matrix Metalloproteinases; D004128:Dimethylnitrosamine