Thioredoxin prolongs survival of B-type chronic lymphocytic leukemia cells

Thioredoxin (Trx) is a ubiquitous protein disulfide oxidoreductase with ant ioxidant, cytokine, and chemotactic properties. Previously, we showed that Trx, in synergy with interleukin 1 (IL-1), IL-2, IL-4, tumor necrosis facto r alpha (TNF-alpha), and CD40-ligation induced S-phase entry and mitosis in normal B cells and B-type chronic lymphocytic leukemia (B-CLL) cells. The viability of B-CLL cells stimulated by these protocols is high, and it has been hypothesized that the overexpression of Bcl-2 found in B-CLL protects the cells from apoptosis in vitro and in vivo. In this study, we have analy zed the response of cells derived from 12 samples of patients with B-CLL to recombinant human Tr:in spontaneous apoptosis, with special reference to t he Bcl-2 expression. Long-term cultures of B-CLL clones showed significantl y higher viability when supplemented with human Trx (P = .031), also exempl ified with clones surviving more than 2 months. Short-term cultures of B-CL L cells exposed to 1 mu g/mL of Trx for 1, 5, or 12 days maintained express ion or delayed down-regulation of Bcl-2 compared with control cultures cont aining RPMI 1640 medium and 10% fetal calf serum only (P = .032, .002, .026 , respectively). All B-CLL cells expressed constitutive Trx at varying but low levels, in contrast to adult T-cell leukemias, which overexpress Trx, a s previously reported. We found that Trx added to B-CLL cells increased in a dose-dependent fashion the release of TNF-alpha, which has been suggested to be an autocrine growth factor for these cells. In conclusion, we have f ound that human recombinamt Trx induced TNF-alpha secretion, maintained Bcl -2, and reduced apoptosis in B-CLL cells. (C) 2000 by The American Society of Hematology.