An Intra-Hepatic TH2 Cytokine Predominance Promotes the Development of PBC-Induced Cirrhosis

The intra-hepatic cytokine imbalance resulting from chronic inflammation promotes fibrogenesis/cirrhosis. Liver pathology in Primary Biliary Cirrhosis (PBC) has been associated with a progressive shift to an inflammatory or Th1-dominant hepatic cytokine profile. However, murine fibrosis models suggest Th2 (anti-inflammatory) but not Th1-cytokines are fibrogenic. We therefore determined the Th1/Th2 hepatic cytokine profile associated with PBC-induced cirrhosis. Normal liver biopsies (n=14) were obtained from donor organs prior to liver transplantation. PBC cirrhotic liver (n=10) was obtained at time of liver transplantation for end-stage liver disease. Liver was snap-frozen, powdered, soluble protein extracted and cytokines measured by ELISA. Pro-inflammatory cytokines IL-12/IL-18 were significantly increased in PBC compared to normal liver (p<0.05). Th1 cytokines IFN-γ/IL-2 were also increased (p<0.05), suggesting a Th1 shift. However, a 10 fold increase was observed for the Th2/regulatory cytokine IL-10 in PBC liver (p<0.05). This increase in IL-10 reversed the IFN-γ:IL-10 ratio observed in normal liver, suggesting Th2 predominance in PBC. Of interest, anti-inflammatory cytokines IL-13/TGF-β, known fibrogenic agents, were significantly reduced in PBC-liver (p<0.05). Use of IL-10 as an anti-fibrogenic agent is currently being investigated, however, our results suggest that chronic overproduction of IL-10 may promote fibrosis. These findings have important implications for our understanding of the mechanisms involved in and the treatment of fibrosis/cirrhosis.