Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 13 November 2007
Vol. 2007, Issue 412, p. tw416
[DOI: 10.1126/stke.4122007tw416]


Toll-Like Receptors LPS and Liver Fibrosis

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

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-beta (TGF-beta), 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-{alpha}1 promoter] did not induce GFP production or myofibroblast differentiation but sensitized them to TGF-beta treatment. DNA microarray analysis showed that Bambi (encoding bone morphogenetic protein and activin membrane-bound inhibitor), a pseudoreceptor that binds to TGF-beta but does not signal, was the only TGF-beta-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-beta, 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-beta 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]

Citation: J. F. Foley, LPS and Liver Fibrosis. Sci. STKE 2007, tw416 (2007).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882