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Tumor necrosis factor stimulates DNA synthesis of mouse hepatocytes in primary culture and is suppressed by transforming growth factor β and interleukin 6
Author(s) -
Satoh Motonobu,
Yamazaki Masatoshi
Publication year - 1992
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041500118
Subject(s) - hepatocyte , dna synthesis , tumor necrosis factor alpha , epidermal growth factor , liver regeneration , aphidicolin , biology , microbiology and biotechnology , interleukin , endocrinology , medicine , cytokine , transforming growth factor , in vitro , cell culture , immunology , biochemistry , regeneration (biology) , genetics
In a previous study, we revealed that tumor necrosis factor (TNF) was secreted in mouse liver at an early phase of liver regeneration after partial hepatectomy. Here, we investigated direct actions of TNF on the in vitro DNA synthesis of adult mouse hepatocytes in primary culture. TNF enhanced both 3 H‐TdR uptake and the number of 3 H‐TdR‐labeled nuclei of hepatocytes. Their time courses were similar to those by epidermal growth factor (EGF) with about a 15 h lag period and a peak period of 24–48 h. This action of TNF was abrogated by DNA polymerase α inhibitor, aphidicolin and blocked specifically by anti‐TNF antibody. The actions of rm TNF were not distinguishable; ED50 was about 7.5U/ml (5ng/ml) and 30U/ml (20ng/ml) for maximal response (about 2‐fold or more of control). Other inflammatory monokines showed differential effects on in vitro DNA synthesis of hepatocyte. Neither type of interleukin 1 affected hepatocyte DNA synthesis in the range examined (up to 50 ng/ml). IL‐6 markedly inhibited the hepatocyte DNA synthesis stimulated by TNF and EGF. The action of TNF was completely suppressed by transforming growth factor β, which is known as a potent inhibitor of hepatocyte growth. Interferon γ also blocked this TNF action when added simultaneously. These results indicate that the activation of tissue macrophages and local secretion of TNF in liver after partial hepatectomy is of physiological importance in liver regeneration, in part by a direct stimulation of hepatocyte DNA synthesis. Cytokines induced by TNF may also participate in the later termination of liver regeneration.