Increase of chemokine interferon-inducible protein-10 (IP-10) in the serum of patients with autoimmune liver diseases and increase of its mRNA expression in hepatocytes

Abstract

To clarify the role of IP-10 in autoimmune liver diseases, we studied the serum levels of IP-10 in 14 patients with autoimmune hepatitis (AIH), 23 patients with primary biliary cirrhosis (PBC), and 65 patients with chronic viral hepatitis (20 type B and 45 type C). The hepatic expression of IP-10 mRNA and the correlation between the serum levels of IP-10 and clinical parameters were also evaluated. In addition to 20 healthy controls, 16 rheumatoid arthritis (RA) patients were included as an extrahepatic inflammatory disease. The serum level of IP-10 was significantly (P < 0.02) higher in patients with AIH, PBC, and chronic hepatitis B and C than in healthy controls, and it was significantly correlated (P < 0.05) with the serum levels of aspartate aminotransferase and alanine aminotransferase in patients with AIH, PBC, and chronic hepatitis B and C. The serum level of IP-10 was not elevated in RA patients. After successful treatment of AIH and chronic hepatitis C, the serum level of IP-10 decreased to the same level as in healthy volunteers. As we previously showed in cases with chronic hepatitis B or C, in situ hybridization in both AIH and PBC cases demonstrated the expression of IP-10 mRNA in hepatocytes around focal or lobular necrosis surrounded by infiltrating mononuclear cells, whereas IP-10 mRNA was not expressed in areas around the damaged bile ducts in PBC cases. The present results suggest that IP-10 is specifically produced by hepatocytes in inflammatory areas irrespective of the aetiology of hepatitis, and that IP-10 may help to recruit T cells to the hepatic lesions in autoimmune liver diseases as well as in chronic viral hepatitis.

Fig. 1

The cDNA sequence of human IP-10. The underlined nucleotides at positions between 144 and 714 were used for the antisense and sense probe (571 bp).

Fig. 2

The serum levels of IP-10 in healthy controls, Chronic hepatitis C (CHC). Chronic hepatitis B (CHB), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and rheumatoid arthritis (RA) patients. The bars show mean ±s.d. in each group.

Fig. 3

The serum levels of IP-10 were compared in 45 chronic hepatitis C (CHC) patients divided into three groups classified by the method of Desmet et al. [19]. Minimal to mild = minimal hepatitis or mild hepatitis; Moderate = moderate hepatitis; Severe = severe hepatitis. The bars show mean ±s.d. in each group. *P < 0·05; **not significant.

Fig. 4

(a) Changes in the serum levels of IP-10 in autoimmune hepatitis (AIH) patients who received prednisolone therapy (n = 14). Before therapy, before prednisolone therapy; after resolution, after successful prednisolone therapy. (b) Changes in the serum levels of IP-10 in chronic hepatitis C (CHC) patients who showed complete response to the IFN therapy (n = 24). Before IFN, before IFN therapy; 3 M after IFN, 3 months after the completion of IFN therapy; 12 M after IFN, 12 months after the completion of IFN therapy. *P < 0·0001.

Fig. 5

Representative results of in situ hybridization analysis of IP-10 mRNA expression in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) patients. A liver section of AIH, around the intralobular necrosis, hybridized with antisense probe (a,b) and sense probe (c) for IP-10. (× 400, original mag.) A liver section of PBC, around the intralobular necrosis, hybridized with antisense probe (d,e) and sense probe (f) for IP-10 (× 400, original mag.). A liver section of AIH, portal and periportal area, hybridized with antisense probe (g,h) (× 200, original mag.). A liver section of PBC, portal and periportal area, hybridized with antisense probe (i,j) (× 200, original mag.). Light field microscopy is shown in (a,d,g,i); dark field microscopy is shown in (b,c,e,f,h,j). The arrows indicate intralobular infiltration of mononuclear cells, the arrowheads show damaged bile ducts, and the asterisks show portal areas.