Effect of IL-4 and IL-13 on collagen production in cultured LI90 human hepatic stellate cells

Background: Recently, it has been reported that interleukin 4 (IL-4) and 13 (IL-13) directly activate fibroblasts and promote fibrosis. In the process of hepatic fibrosis, the effects of these cytokines on hepatic stellate cells (HSCs) are not well known. Methods: We evaluated the effects of IL-4 and IL-13 on the collagen production and the proliferation of LI90, a hepatic stellate cell line. We also examined whether interferon (IFN) interferes with the expression of collagen, since IFN has been reported to clinically suppress hepatic fibrosis. Results: The receptor complex for IL-4 and IL-13 was IL-4R alpha/IL-13R alpha 1 on LI90 cells, and the phosphorylation of Stat6 was induced by IL-4 and IL-13. The treatment of LI90 cells with IL-4 or IL-13 increased the production of collagen I protein levels by nearly three times in comparison with untreated cells. Collagen mRNA levels were increased roughly 10-fold by IL-4 and 100-fold by IL-13. Interestingly, BrdU incorporation in LI90 cells was decreased by IL-4 or IL-13 treatment. Furthermore, induction of collagen I production by these cytokines was blocked by IFN alpha or IFN beta treatment, although neither treatment alone suppressed collagen production. Conclusions: Our data suggested that IL-4 and IL-13 directly affected HSCs by increasing collagen production and suppressing cell proliferation. The anti-fibrogenetic effect of IFN may be due in part to the blockade of IL-4 and IL-13 stimulation of HSCs.