Deletion of interleukin (IL)‐12p35 induces liver fibrosis in dominant‐negative TGFβ receptor type II mice

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease characterized by destruction of intrahepatic small bile duct biliary epithelial cells (1). The serological hallmark of PBC is the presence of anti-mitochondrial auto-antibodies (AMA) directed against the pyruvate dehydrogenase E2 complex (PDC-E2) located within the inner membrane of mitochondria (2–4). We previously reported that mice transgenic for directed expression of a dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII), under the control of the CD4 promoter lacking the CD8 silencer, spontaneously develop an autoimmune biliary ductular disease (5). This disease is associated with the spontaneous production of AMAs directed to the same mitochondrial autoantigens recognized by sera from PBC patients (6) with lymphocytic liver in ltration and periportal in ammation analogous to human PBC. The murine serum cytokine pro le is similar to sera of patients with PBC. These findings indicate that the dnTGFβRII mice are a useful animal model for studying the pathogenic mechanisms of human PBC. We have demonstrated that deleting the p40 chain of IL-12 from dnTGFβRII mice produced a marked diminution in the levels of proinflammatory Th1 cytokines in livers with accompanying reductions in cellular infiltrates in portal tracts and diminished bile duct damage (7). IL-12, the prototypic member of the heterodimeric family of cytokines, consists of a p40 and a p35 subunit covalently linked by two disulfide linkages. Both p35 and p40 are components of two heterodimeric cytokines in the IL-12 family (8). In order to further examine and differentiate the role of the p35- and p40-containing members of the IL-12 cytokine family in dnTGFβRII disease, we generated an IL-12p35−/− mouse strain on the dnTGFβRII background. Our results indicate that in contrast to the IL-12p40−/− mice that were protected from liver inflammation, the IL-12p35−/− mice developed liver inflammation with similar severity but delayed onset compared to the parental dnTGFβRII mice. The p35−/− mice demonstrate a distinct cytokine profile, with enhanced IL-17, compared to parental dnTGFβRII and p40−/− mice. Strikingly, the deletion of IL-12p35 subunit from dnTGFβRII mice resulted in frequent development of liver fibrosis. This model is unique in that it has resemblance to a number of immunological and histological features of human PBC. Although we do not opine that it recapitulates PBC faithfully, we submit that it is a useful system to dissect the cellular and molecular basis of loss of tolerance and liver damage.