2, 3 We therefore set out to examine the contribution of CX3CL14–9 to the bile duct destruction of PBC. Our previous findings in PBC indicated that CX3CL1 is elevated in serum concurrent with increased expression of the CX3CR1 receptor in liver-infiltrating mononuclear cells (LMCs),10 leading us to posit that CX3CL1 could indeed be critical for the generation and persistence of the portal lymphocytic infiltration in C59 wnt PBC. We have herein taken advantage of our ability to isolate pure

populations of multiple intrahepatic cell types, including endothelial cells (ECs), liver sinusoidal endothelial cells (LSECs), and biliary epithelial cells (BECs) to directly study the interaction of CX3CL1-producing cells with LMCs. We should note that several nonprofessional immunocompetent cells produce chemokines in response to ligands for Toll-like receptors (TLRs).11, 12 Here we have evaluated CX3CL1 production from ECs, LSECs, and BECs exposed to TLR ligands and report that ECs produced

high amounts of CX3CL1 using one or another of several TLR ligands, whereas LSECs never produced CX3CL1 with any ligand; BECs produced CX3CL1 on exposure to autologous LMCs, tumor necrosis factor α (TNF-α), and a TLR3 ligand. In the process of simplifying the production www.selleckchem.com/products/H-89-dihydrochloride.html system of CX3CL1 from BECs, we found that TLR3-stimulated BECs produced CX3CL1 after direct contact with TLR4-stimulated autologous monocytes. In conclusion, our data indicate that CX3CL1 and TNF-α, which are induced by TLR ligands, participate in processes that lead to disease-specific recruitment of lymphoid cells into the portal tracts of the liver and thereby to the characteristic chronic nonsuppurative destructive cholangitis of PBC. This new knowledge of the mechanisms of lymphocyte homing

and recruitment induced by innate immunity and, potentially, the ability to inhibit abnormal chemoattractant homing is a fertile area for future therapeutic intervention in PBC. BEC, biliary epithelial cell; EC, endothelial cell; IFN-γ, interferon-γ; LMC, liver-infiltrating mononuclear cell; LPS, lipopolysaccharide; LSEC, liver sinusoidal endothelial cell; LTA, lipoteichoic acid; mDC, myeloid dendritic cell; NK, natural killer; NKT, natural killer T; PBC, primary biliary cirrhosis; Rebamipide poly(I:C), polyinosinic:polycytidylic acid; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α. Twenty-one explanted livers were studied, derived from nine patients with PBC—three with hepatitis B virus infection, seven with hepatitis C virus infection, and two with primary sclerosing cholangitis. All patients had end-stage liver cirrhosis without signs of other acute liver injury from an unrelated cause. The diagnosis of PBC was based on established criteria13 and all such patients had a positive test for serum antimitochondrial antibodies.