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.


OBJECTIVE
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 (IFNgamma), interleukin 1beta (IL-1beta), IL-6, IL-18, tumour necrosis factor alpha (TNFalpha), and macrophage inflammatory protein 1beta (MIP1beta)). 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. IFNgamma and IL-18 mRNA levels were highly correlated and significantly upregulated in chronic hepatitis and cirrhotic tissue versus controls. TNFalpha mRNA was upregulated in chronic hepatitis without cirrhosis, while IL-6 mRNA was significantly downregulated. IL-1beta, IL-6, and MIP1beta mRNA levels were significantly correlated with portal tract MAC387(+) cell density.


CONCLUSIONS
The significant upregulation of IFNgamma and IL-18 mRNA and significant correlations between IFNgamma 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.
McGuinness
P H
PH
The A W Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, Australia.
Painter
D
D
Davies
S
S
McCaughan
G W
GW
D000328:Adult; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D054407:Chemokine CCL4; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics; D008099:Liver / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D054407:Chemokine CCL4; D007371:Interferon-gamma; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule