Synthesis of interleukin-1β in primary biliary cirrhosis: Relationship to treatment with methotrexate or colchicine and disease progression



Primary biliary cirrhosis (PBC) is a chronic, progressive, cholestatic liver disease. Interleukin-1β (IL-1β) may play a role in the pathogenesis of PBC by contributing to altered immune function and fibrosis. Colchicine or methotrexate has some beneficial effects in the treatment of PBC, and also affects interleukin-1 (IL-1). Therefore, we prospectively studied the synthesis of IL-1β by peripheral blood mononuclear cells (PBMC) from 42 patients with PBC entered into a randomized, doubleblind, double-dummy controlled trial of colchicine and methotrexate. PBMC obtained at entry, 6, 12, 18, and 24 months were stimulated to produce IL-1β with phytohemagglutinin (PHA), lipopolysaccharide (LPS), Staphylococcus epidermidis, recombinant IL-2, or mitochondrial antigen. Patients in the two treatment groups did not differ at entry in biochemical measures or liver histological stage. Over 24 months in both groups, serum bilirubin and histologic stage remained stable and alkaline phosphatase decreased significantly. For all patients, synthesis of IL-1β increased constitutively and in response to immune-mediated stimulants (PHA, IL-2, and mitochondrial antigen) but not the bacterial stimulants LPS or S epidermidis. Compared with levels of IL-1β at entry, PHA induced increases for patients treated with methotrexate (12, 18, and 24 months) or colchicine (18 and 24 months). At 24 months, IL-2-induced IL-1β synthesis was increased in patients treated with methotrexate, whereas S epidermidis-induced IL-1β was enhanced in colchicine-treated patients. Before treatment, IL-1β production did not relate to severity of disease except in response to S epidermidis. Notably, in patients with stable or improving liver histological stage, IL-1β synthesis increased dramatically at 12 months in response to IL-2 and S epidermidis, and also to LPS by 24 months. Alterations in IL-1β synthesis in patients with PBC may reflect underlying immunoregulatory changes that contribute to disease progression or stabilization. (Hepatology 1995;22:518–524.)