Differential effects of interleukin‐1α, tumor necrosis factor α, and transforming growth factor β1 on cell proliferation and collagen formation by cultured fat‐storing cells

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Abstract
Fat-storing cells (FSCs), perisinusoidal cells which normally participate in metabolism of vitamin A, have been suggested to participate in collagen synthesis in fibrotic liver. However, key mediators which regulate collagen metabolism in FSCs are yet to be elucidated. In fibroblasts, Interleukin-1 (IL-1), Tumor Necrosis Factor .alpha. (TNF.alpha.), and Transforming Growth Factor .beta. (TGF.beta.) have been shown to induce diverse modulations of collagen metabolism and cell proliferation. In the present study, these cytokines were tested for their abilities to regulate collagen formation and proliferation by cultured rat FSCs. FSCs primary culture was established and incubated in the absence or presence of various concentrations of IL-1.alpha., TNF.alpha., and TGF.beta.1. Tritiated proline and thymidine were used to examine collagen formation and cell proliferation. IL-1.alpha. (2.5-10 U/ml) had a concentration-dependent stimulatory effect on FSC proliferation with a maximal response of 160% compared to that of untreated PSCs. This mitogenic effect resulted in slight but significant increases (15-20%) in the net collagen formation. However, when this parameter was standardized relative to DNA content, significant inhibition of both collagen and noncollagen protein formation by IL-1.alpha. was demonstrated. TNF.alpha. also exhibited a similar mitogenic effect but induced a more selective inhibition of collagen formation. In contrast, TGF.beta.1 (0.01 ng/ml) specifically enhanced collagen formation by 60-80%, as also evidenced by significant increases in the ratio of [3H]hydroxyproline to [3H]proline incorporated in newly formed proteins. Unlike IL-1.alpha. or TNF.alpha., TGF.beta.1 significantly inhibited FSC proliferation, and this inhibition was correlated (p < 0.05) with the enhancement of collagen accumulation in the medium induced by this cytokine. These data suggest that regulation of collagen production and proliferation of FSCs can be mediated through independent mechanisms, and these mediators with differential effect may play important roles in liver fibrogenesis. In particular, TGF.beta.1 may be of pathobiological importance in inducing collagen accumulation and possibly inhibiting differentiation of FSCs.