Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection

Background-Upregulation of Th1 associated intrahepatic cytokines in chronic hepatitis C virus (HCV) infection should lead to a significant non-specific cellular immune response, a prerequisite for viral clearance. However, to date, the role of this non-specific response in HCV has been understudied. Aims--To analyse the intrahepatic macrophage activity in chronic HCV infection by immunostaining and by quantitation of cytokine mRNA. Methods--HCV positive liver tissues (chronic hepatitis, n = 10; cirrhosis, n = 5) were immunostained for CD68, MAC387, and semiquantitated by polymerase chain reaction for intrahepatic cytokine mRNAs (interferon gamma (IFN gamma), interleukin 1 beta (IL-1 beta), IL-6, IL-18, tumour necrosis factor alpha (TNF alpha), and macrophage inflammatory protein 1 beta (MIP1 beta)). HCV negative normal liver tissues (for cytokines, n = 6; for immunostaining, n = 5) were included as controls. Results--MAC387(+) cells were focally increased in areas of erosion at the limiting plate while lobular staining was minimal. CD68(+) staining was diffuse in both portal (increased in HCV) and lobular areas. The portal tract (mean) density of CD68(+) and MAC387(+) cells was significantly increased in patients with HCV compared with normal tissue. IFN gamma and IL-18 mRNA levels were highly correlated and significantly upregulated in chronic hepatitis and cirrhotic tissue versus controls. TNF alpha mRNA was upregulated in chronic hepatitis without cirrhosis, while IL-6 mRNA was significantly downregulated. IL-1 beta, IL-6, and MIP1 beta mRNA levels were significantly correlated with MAC387(+) cell density. Conclusions--The significant upregulation of IFN gamma and IL-18 mRNA and significant correlations between IFN gamma and other proinflammatory cytokines, suggest a Th1/cell mediated intrahepatic immune response in chronic HCV infection. However, further clarification of the cellular sources of these cytokines is required.