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Regulates Transforming Growth Factor- Expression in Regenerating Murine Liver and Isolated Hepatocytes
*
Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505; and
Tanabe Seyaku Co. Ltd. Kawagishi, Tada, Japan
TNF-
is a pleotropic proinflammatory cytokine that has
been implicated as a contributing factor in a number of disease
processes, primarily through its ability to induce the expression of
inflammatory and cytotoxic mediators. TNF- is also involved in cell
growth accompanying the healing process in multiple organ systems and
influences liver repair following hepatotoxic damage or regeneration
following partial hepatectomy. In this respect, TNF- is a known
mitogen for hepatocytes. In this paper we describe a novel role for
TNF- in the modulation of expression of TGF-, the latter being a
complete hepatocyte mitogen. TNF- directly up-regulates TGF- mRNA
by up to 7-fold in isolated mouse hepatocytes, whereas neutralization
of TNF- significantly decreased liver mRNA and protein expression of
TGF- following chemical-induced hepatotoxicity. That TNF-
directly stimulated TGF- was suggested by the inability of either
anti-IL-6 Abs or cycloheximide to inhibit TNF--induced TGF-
expression in hepatocytes. However, in the presence of anti-TGF-
neutralizing Abs, the mitogenic activity of TNF- is abrogated. Using
cells transfected with the TGF- promoter, and an RNA polymerase
inhibitor, it was shown that TNF- modulates TGF- expression
through both pre- and posttranscriptional events. Taken together, these
data suggest that TNF- participates in liver repair and
regeneration, in part, by directly inducing the expression of
TGF-.
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