A protective role of macrophage-migration inhibitory factor (MIF) in toxically induced liver fibrosis

Liver fibrosis is a wound healing response to chronic liver injury which is associated with excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cells (HSCs) are the main ECM-producing cells during liver fibrosis and have been considered to play a key role in this context. Owing to their potent chemotactic and immunoregulatory properties, chemokines contribute to the development of liver fibrosis. Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine, which has recently been recognized to function as a chemokine-like function (CLF) cytokine in chronic inflammatory diseases. A contribution of MIF to liver fibrosis has been has not yet been systematically investigated. To address this question, we compared mif^-/- with wild-type mice in the CCl₄-induced fibrosis model. Remarkably, histological (Sirius red staining) analysis as well as hepatic hydroxyproline content (P <0.01), collagen expression and the expression of tissue inhibitors of metalloproteinases (TIMPs) and TGF-β1 (all P <0.01) revealed a considerably stronger fibrotic response in the mif^-/- mice compared to wild-type mice. These data were confirmed in an independent model, i.e. when inducing liver fibrosis with thioacetamide (TAA) for six weeks. Given the well-established pro-inflammatory spectrum of MIF activity in various diseases, this unexpectedly, yet clearly, suggested a protective role of MIF during the progression of liver fibrosis in these two models. To unravel the underlying molecular mechanisms we have already detected the functional MIF receptors CD74, CXCR2 and CXCR4 on hepatic stellate cells and currently investigate the relevant intracellular signalling pathways in several hepatic cell types mediating the protective effect of MIF in toxically induced liver fibrosis.

MIF - cytokines - fibrosis