SYNTHESIS OF INTERLEUKIN-1-BETA 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-1 beta (IL-1 beta) may play a role in the pathogenesis of PBC by contributing to altered immune function and fib rosis. Colchicine or methotrexate has some beneficial effects in the t reatment of PBC, and also affects interleukin-1 (IL-1). Therefore, we prospectively studied the synthesis of IL-1 beta by peripheral blood m ononuclear cells (PBMC) from 42 patients with PBC entered into a rando mized, double-blind, double dummy controlled trial of colchicine and m ethotrexate. PBMC obtained at entry, 6, 12, 18, and 24 months were sti mulated to produce IL-1 beta with phytohemagglutinin (PHA), lipopolysa ccharide (LPS), Staphylococcus epidermidis, recombinant IL-2, or mitoc hondrial 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 s table and alkaline phosphatase decreased significantly. For all patien ts, synthesis of IL-1 beta 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 leve ls of IL-1 beta at entry, PHA induced increases for patients treated w ith methotrexate (12, 18, and 24 months) or colchicine (18 and 24 mont hs). At 24 months, IL-2-induced IL-1 beta synthesis was increased in p atients treated with methotrexate, whereas S epidermidis-induced IL-1 beta was enhanced in colchicine-treated patients. Before treatment, IL -1 beta production did not relate to severity of disease except in res ponse to S epidermidis. Notably, in patients with stable or improving liver histological stage, IL-1 beta synthesis increased dramatically a t 12 months in response to IL-2 and S epidermidis, and also to LPS by 24 months. Alterations in IL-1 beta synthesis in patients with PBC may reflect underlying immunoregulatory changes that contribute to diseas e progression or stabilization.