Rat hepatic stellate cells contribute to the acute-phase response with increased expression of alpha 1(I) and alpha 1(IV) collagens, tissue inhibitorof metalloproteinase-1, and matrix-metalloproteinase-2 messenger RNAs

The acute-phase response (APR) represents a systemic reaction of the organi sm to multiple nonspecific inflammatory stimuli. In general, it is protecti ve for the host, and hepatocytes are the main cells responding with alterat ions in the expression of a set of liver-specific proteins named the acute- phase proteins. We have previously shown that although a turpentine-induced APR is not fibrogenic per se, it enhances collagen deposition in rats trea ted with CCl4 and up-regulates expression of hepatic alpha1(I) collagen and tissue inhibitor of metalloproteinases 1 (TIMP-1) messenger RNAs (mRNAs). In this report we extended our studies and showed that turpentine induced, in a time-dependent manner, expression of alpha1(I) and alpha1(IV) collagen s, TIMP-1, and matrix-metalloproteinase 2 (MMP-2) mRNAs, We further showed that expression of these mRNAs occurs in hepatic stellate cells, but not in hepatocytes obtained 6 hours after the induction of an APR episode. These changes were accompanied by increased blood levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) without noticeable immediate ch anges in the expression of their respective mRNAs in the liver. In contrast to CCl4-induced liver damage, turpentine alone, whether administered as a single dose or as a weekly dose for 3 weeks did not up-regulate expression of transforming growth factor beta1 (TGF-beta1) mRNA and did not result in excess collagen deposition. Overall, these findings suggest that collagen d eposition in the livers of rats with repeated APR episodes may be enhanced only when given together with a fibrogenic stimulus that activates hepatic stellate cells (HSCs) and/or up-regulates TGF-beta1 mRNA expression.