1, 2 Chemokines (chemotactic cytokines) are essential mediators for attracting immune cells and for activating nonparenchymal liver cells.3, 4 As such, circulating Gr1-expressing monocytes are massively recruited after liver injury in mice by mechanisms dependent on chemokine (C-C motif) receptor 2 (CCR2) and its main ligand, monocyte chemoattractant protein 1 (MCP1).5-7 These monocytes differentiate into hepatic macrophages and promote the progression of liver fibrosis by releasing proinflammatory and profibrogenic www.selleckchem.com/products/Bortezomib.html cytokines such as tumor necrosis factor
(TNF) and transforming growth factor β and by directly activating collagen-producing HSCs.5 The chemokine fractalkine [chemokine (C-X3-C motif) ligand 1 (CX3CL1)] differs from other chemokines in several respects. First, it is the only member of the CX3C chemokine Tanespimycin supplier family and lacks redundancy because there is only one known receptor, chemokine (C-X3-C motif) receptor 1 (CX3CR1), corresponding to this chemokine. Second, CX3CL1 is
synthesized as a transmembrane protein with its chemokine domain presented on an extended mucin-like stalk; this allows tight, integrin-dependent adhesion of CX3CR1-expressing leukocytes.8 In addition, constitutive and inducible cleavage by metalloproteinases can result in the release of soluble CX3CL1 fragments from the cell membrane and thereby act as classic soluble chemoattractants.9 selleck products The fractalkine receptor, CX3CR1, is primarily expressed on circulating monocytes, tissue macrophages, and tissue dendritic cell populations but is also expressed on T cell and natural killer cell subsets.10 In the liver, CX3CR1 expression has been described on the biliary epithelium, infiltrating mononuclear cells, HSCs, and even hepatoma cell lines.11,
12 Preliminary observations have linked fractalkine and its receptor CX3CR1 to the pathogenesis of chronic liver diseases. Fractalkine and CX3CR1 were found to be up-regulated in biopsy samples of patients with acute and chronic liver injury11 and especially cholestatic diseases.13, 14 Furthermore, CX3CR1 gene polymorphisms have been associated with fibrosis progression in patients with chronic hepatitis C.12 Experimentally, the shedding of CX3CL1 by HSCs has promoted the chemoattraction of monocytes in vitro,15 and the adhesion of human CD16+ monocytes to liver sinusoidal endothelium is partially mediated by CX3CR1.16 Therefore, we conducted experiments to define the roles of fractalkine and CX3CR1 in liver inflammation and fibrosis.