Background: In response to nonspecific inflammatory stimuli, circulating monocytes produce several cytokines that regulate the expression of liver acute phase protein genes. Patients with alcoholic liver disease have several manifestations of the acute phase response, including elevated serum levels of interleukin (IL)-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha). However, the role of the acute phase response on liver fibrogenesis has not been explored.
Experimental design: In this communication we report experiments performed to investigate whether turpentine, an acute phase response inducer in rats has any effect on alpha 1 (I) procollagen gene expression in the liver. We also investigated which of the cytokines is responsible for the turpentine effect and whether IL-6 and TNF-alpha had an effect on alpha 1 (I) procollagen mRNA expression by liver fat-storing cells (FSC).
Results: We show that alpha 1 (I) procollagen mRNA is increased in livers of turpentine-treated rats, and that an antibody to IL-6 as well as colchicine 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 transforming growth factor-beta and fibronectin mRNAs. TNF-alpha inhibits alpha 1 (I) procollagen expression in FSC by 24 to 48 hours. However, TNF-alpha 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 response, alone or in conjunction with other cytokines, could play an important role in liver fibrogenesis by inducing the expression of collagen, fibronectin, and transforming growth factor-beta mRNAs in FSC.