Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver

The role played by chemokines in regulating the selective. recruitment of l ymphocytes to different tissue compartments in disease is poorly characteri zed, In hepatitis C infection, inflammation confined to portal areas is ass ociated with a less aggressive course, whereas T cell infiltration of the l iver parenchyma is associated with progressive liver injury and cirrhosis, We propose a mechanism to explain how lymphocytes are recruited to hepatic lobules during bursts of necroinflamnatory activity in chronic hepatitis C infection, We report here that lymphocytes infiltrating hepatitis C-infecte d liver express high levels of the chemokine receptors CCR5 and CXCR3. Howe ver, whereas the CCR5 ligands macrophage inflammatory protein-1 alpha and - 1 beta were largely confined to vessels within portal tracts, the CXCR3 lig ands IFN-inducible protein-ill and monokine-induced by IFN-gamma were selec tively up-regulated on sinusoidal endothelium. In vitro, human hepatic sinu soidal endothelial cells secreted IPN-inducible protein-10 and monokine-ind uced by IFN-gamma in response to stimulation with IFN-gamma in combination with either IL-I or TNF-alpha. This suggests that intrahepatic Th1 cytokine s drive the increased expression of IFN-inducible protein-10 and monokine-i nduced by IFN-gamma and thereby promote the continuing recruitment of CXCR3 -expressing T cells into the hepatic lobule in chronic hepatitis C infectio n.