Transforming growth factor β1-regulated gene expression of Ito cells

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During liver fibrogenesis, Ito cells are regarded as the principal matrix synthesizing cells and transforming growth factor β 1 (TGF-β 1) appears to be the main fibrogenic mediator. This study analyzed the effects of TGF-β 1 on Ito cell activation, proliferation, and on the expression of a set of matrix proteins, antiproteases, and TGF-β receptors both in “early cultured” and “culture-activated” Ito cells. Rat liver Ito cells at day 2 of primary culture (“early cultured” cells) were mainly smooth muscle α actin (SMA)-negative, whereas cells at day 6 were judged as “activated” cells (SMA-positive). Following 24-hour exposure to 1 ng/mL TGF-β1, total protein synthesis, cell proliferation, and expression of the “activation” marker SMA were not significantly changed. In addition to previously described stimulatory effects on collagen types I and III, fibronectin, undulin, and proteoglycan-gene expression, TGF-β also dose-dependently increased synthesis and secretion of tenascin, laminin, entactin, collagen type IV, and α2-macroglobulin, but decreased C1-esterase inhibitor production by Ito cells, as revealed by immunoprecipitation of endogenously labeled proteins and by Northern blot analysis. The stimulatory effect of TGF-β was evident both in “early cultured” as well as “culture-activated” Ito cells. By reverse- transcription polymerase chain reaction (RT-PCR) analysis, TGF-β type II, III, and TGF-β/activin type I receptors were present in Ito cells, and their expression pattern was not changed upon TGF-β exposure. Northern blot analysis demonstrated that type I TGF-β/activin receptor was induced during in vitro activation and that TGF-β exposure resulted in a slight increase of type I and III receptor messenger RNAs. In summary, the data illustrate that TGF-β is an important fibrogenic mediator acting both on “early cultured” as well as “culture-activated” Ito cells, rather than a mitogenic or morphogenic mediator. The differential regulation of TGF-β/activin receptors during in vitro activation and their up-regulation by TGF-β1 might represent a mechanism by which the receptor complex regulates TGF-β signalling in Ito cells.