INDUCTION OF AN ACUTE-PHASE RESPONSE IN RATS STIMULATES THE EXPRESSION OF ALPHA-1(I) PROCOLLAGEN MESSENGER-RIBONUCLEIC-ACID IN THEIR LIVERS- POSSIBLE ROLE OF INTERLEUKIN-6

BACKGROUND: In response to nonspecific inflammatory stimuli, circulati ng monocytes produce several cytokines that regulate the expression of liver acute phase protein genes. Patients with alcoholic liver diseas e have several manifestations of the acute phase response, including e levated serum levels of interleukin (IL)-1 (IL-1), IL-6 and tumor necr osis factor-alpha (TNF-(alpha)). However, the role of the acute phase response on liver fibrogenesis has not been explored. EXPERIMENTAL DES IGN: In this communication we report experiments performed to investig ate whether turpentine, an acute phase response inducer in rats has an y effect on alpha 1(I) procollagen gene expression in the liver. We al so investigated which of the cytokines is responsible for the turpenti ne effect and whether IL-6 and TNF-alpha had an effect on alpha 1(I) p rocollagen mRNA expression by liver fat-storing cells (FSC). RESULTS: We show that alpha 1(I) procollagen mRNA is increased in livers of tur pentine-treated rats, and that an antibody to IL-6 as well as colchici ne inhibit this effect. We also show that rIL-6 induces the expression of alpha 1(I) procollagen mRNA in cultured FSC but not in hepatocytes . We demonstrated that the IL-6 effect is a transcriptional event that requires ''de novo'' protein synthesis. In addition to its effect on collagen gene expression, rIL-6 also stimulates expression of transfor ming growth factor-beta and fibronectin mRNAs. TNF-alpha inhibits alph a 1(I) procollagen expression in FSC by 24 to 48 hours. However, TNF-a lpha induces a transient expression of alpha 1(I) procollagen mRNA by 2 to 3 hours. This increase is preceded by the induction of IL-6 mRNA. CONCLUSIONS: We conclude that IL-6 produced during the acute phase re sponse, alone or in conjunction with other cytokines, could play an im portant role in liver fibrogenesis by inducing the expression of colla gen, fibronectin, and transforming growth factor-beta mRNAs in FSC.