Lobular - but not periovular - inhibition of collagen deposition in the liver of S-Mansoni infected mice using interferon-gamma

Background/Aims: Interferon-gamma (IFN gamma) elicits anti-proliferative and antifibrogenic activity in a variety of mesenchymal cells, including hepatic stellate cells (Ito cells), and therefore represents a possible drug for liver fibrosis. However, IFN gamma binds to heparan sulfate, and is localized by these molecules in a restricted area within the tissue. For example, in rat liver, it has been shown that following injection, IFN gamma was concentrated in a restricted area by heparan sulfate. The aim of this study was to analyze, at the tissular level in the liver, the antifibrogenic activity of IFN gamma. Methods: Chronic inflammation due to Schistosoma infection induces hepatic fibrogenesis around the parasite eggs (portal fibrosis) and in the parenchyma (lobular fibrosis). Infected mice were treated with recombinant IFN gamma, and the collagen content of the liver was evaluated by means of biochemical dosages, histologic and morphometric examination of liver tissue, and electron microscopic analysis. Results: IFN gamma reduced the whole liver collagen content by 28% compared to control mice. In control mice, collagen was found around eggs and infiltrating the parenchyma, associated with a diffuse array of inflammatory cells, while in treated mice the collagen was present only around eggs and surrounded by a dense layer of inflammatory cells. Therefore, collagen was measured in isolated granulomas and in the remaining parenchyma. We found that IFN gamma strongly reduced the parenchymal collagen (74%), but had no effect on the granuloma collagen content. Conclusions: Together these data demonstrate that IFN gamma did not act in a homogeneous manner in the liver. Since granulomas are almost completely devoid of heparan sulfate, these data could suggest, among others hypotheses, that heparan sulfate which binds IFN gamma either localizes or mediates the cytokine activity outside the granulomas.