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

Abstract

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 γ (IFNγ), interleukin 1β (IL1β), IL-6, IL-18, tumour necrosis factor α (TNFα), and macrophage inflammatory protein lγ (MIP1γ)). 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. IFNγ and IL-18 mRNA levels were highly correlated and significantly upregulated in chronic hepatitis and cirrhotic tissue versus controls. TNFα mRNA was upregulated in chronic hepatitis without cirrhosis, while IL-6 mRNA was significantly downregulated. IL-1β, IL-6, and MIP1β mRNA levels were significantly correlated with portal tract MAC387+ cell density. Conclusions-The significant upregulation of IFNγ and IL-18 mRNA and significant correlations between IFNγ 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.