LPS and Liver Fibrosis

Abstract

Fibrosis, the production of scar tissue, occurs as a result of tissue damage and is associated with inflammation. In the liver, fibrosis is due to Kupffer cells (liver macrophages), which produce transforming growth factor-β (TGF-β), a primary inducer of liver fibrosis, and hepatic stellate cells (HSCs), which differentiate into extracellular matrix-producing myofibroblasts. Because of accompanying stress on the gut wall, liver injury is associated with the increased abundance, in the liver and blood, of the bacterial product lipopolysaccharide (LPS), a ligand for Toll-like receptor 4 (TLR4), so Seki et al . (see the commentary by Friedman) compared liver fibrosis in wild-type and TLR4-mutant mice following liver injury. Immunohistochemical analysis showed that TLR4-mutant mice had less fibrosis than did wild-type mice. Both Kupffer cells and HSCs express TLR4 on their cell surface. In wild-type mice whose Kupffer cells (but not HSCs) were depleted, fibrosis after injury was similar in mice that received bone marrow transplantations from either TLR4-mutant or wild-type mice, indicating that LPS activation of HSCs (but not Kupffer cells) was important for fibrosis. LPS treatment of HSCs isolated from Coll-GFP reporter mice [in which the green fluorescent protein (GFP) gene is controlled by the collagen-α1 promoter] did not induce GFP production or myofibroblast differentiation but sensitized them to TGF-β treatment. DNA microarray analysis showed that Bambi (encoding bone morphogenetic protein and activin membrane-bound inhibitor), a pseudoreceptor that binds to TGF-β but does not signal, was the only TGF-β-related gene whose expression was changed (it was down-regulated) by LPS treatment of HSCs. Thus, LPS in the liver, by decreasing the abundance of Bambi on the surface of HSCs, increases their responsiveness to Kupffer cell-derived TGF-β, leading to enhanced fibrosis. E. Seki, S. De Minicis, C. H. Österreicher, J. Kluwe, Y. Osawa, D. A. Brenner, R. F. Schwabe, TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat . Med . 13 , 1324-1332 (2007). [PubMed] S. L. Friedman, A deer in the headlights: BAMBI meets liver fibrosis. Nat . Med . 13 , 1281-1282 (2007). [PubMed]