Transforming growth factor beta 1 regulates production of acute-phase proteins.

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Abstract
We explored the possible role of transforming growth factor .beta.1 (TGF-.beta.), a cytokine that appears to be an important modulator of inflammation and tissue repair, in regulation of human plasma protein synthesis during the acute-phase response. In Hep 3B cells, TGF-.beta. led to increased secretion of the positive acute-phase proteins .alpha.1-protease inhibitor and .alpha.1-antichymotrypsin and decreased secretion of the negative acute-phase protein albumin. In Hep G2 cells, after incubation with TGF-.beta., the same changes in secretion of .alpha.1-protease inhibitor, .alpha.1-antichymotrypsin, and albumin were observed, as well as decreased secretion of both the negative acute-phase protein .alpha.-fetoprotein and the positive acute- phase protein fibrinogen. In addition, TGF-.beta. modulated the effects of interleukin 6; these cytokines, in combination, were additive in inducing synthesis and secretion of .alpha.1-protease inhibitor and .alpha.1-antichymotrypsin and in decreasing secretion of albumin and .alpha.-fetoprotein. TGF-.beta. inhibited the induction of fibrinogen caused by interleukin 6. The effects of .alpha.1-protease inhibitor were confirmed by metabolic labeling in Hep 3B cells and by demonstrating increased accumulation of specific mRNA in Hep G2 cells, and the effects on fibrinogen were confirmed in Hep 3B cells by studies of mRNA for the .alpha. chain of fibrinogen. TGF-.beta. had no effect on haptoglobin or .alpha.1-acid glycoprotein secretion, either directly or in the presence of interleukin 6, which is capable of inducing these proteins. These studies demonstrate that TGF-.beta. can affect hepatic synthesis and secretion of a subset of acute-phase proteins, both directly and by modulating the effect of interleukin 6. The affected group of plasma proteins is distinct from those affected by other recognized acute-phase protein-inducing cytokines. These findings support the view that combinations of cytokines mediate the response of the hepatocyte to inflammatory stimuli.