Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice.
Tenascin-C (TNC), an extracellular matrix glycoprotein, is upregulated in chronic liver disease. Here, we investigated the contribution of TNC to liver fibrogenesis by comparing immune-mediated hepatitis in wild-type (WT) and TNC-null (TNKO) mice. Eight-week-old BALB/c mice received weekly intravenous injections of concanavalin A to induce hepatitis, and were sacrificed one week after the 3rd, 6th, 9th, and 12th injections. In WT livers, immunohistochemical staining revealed a gradual increase in TNC deposition. TNC mRNA levels also increased sequentially and peaked after the 9th injection. Collagen deposition, stained with picrosirius red, was significantly less intense in TNKO mice than in WT mice, and procollagen I and III transcripts were significantly upregulated in WT mice compared with TNKO mice. Inflammatory infiltrates were most prominent after the 3rd-6th injections in both groups and were less intense in TNKO mice than in WT mice. Interferon-gamma, tumour necrosis factor-alpha, and interleukin-4 mRNA levels were significantly higher in WT mice than in TNKO mice, while activated hepatic stellate cells (HSCs) and myofibroblasts, a cellular source of TNC and procollagens, were more common in WT livers. Transforming growth factor (TGF)-beta1 mRNA expression was significantly upregulated in WT mice, but not in TNKO mice. In conclusion, TNC can promote liver fibrogenesis through enhancement of inflammatory response with cytokine upregulation, HSC recruitment, and TGF-beta expression during progression of hepatitis to fibrosis.
El-Karef
A
A
Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, Mie, Japan.
Yoshida
T
T
Gabazza
E C
EC
Nishioka
T
T
Inada
H
H
Sakakura
T
T
Imanaka-Yoshida
K
K
D000818:Animals; D003208:Concanavalin A; D005260:Female; D006521:Hepatitis, Chronic / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011347:Procollagen / Q000096:biosynthesis; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019063:Tenascin / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
D011347:Procollagen; D019063:Tenascin; D053773:Transforming Growth Factor beta1; D003208:Concanavalin A; D015847:Interleukin-4; D012313:RNA; D007371:Interferon-gamma