Thioredoxin expression in primary T-cell acute lymphoblastic leukemia and its therapeutic implication.

Increased expression of intracellular thioredoxin has been implicated in the inhibition of apoptosis and in a decrease in the sensitivity of the malignancies to drug-induced apoptosis. In the present studies, we analyzed expression of thioredoxin in samples from 28 children with T-cell acute lymphoblastic leukemia and analyzed their sensitivity toward inhibition of thioredoxin expression. Thioredoxin was expressed in variable amounts. Higher expression was associated with higher WBC counts. Exogenously added thioredoxin stimulated proliferation of clonogenic cells among the T-cell acute lymphoblastic leukemia samples expressing relatively lower levels of intracellular thioredoxin, whereas there was no effect on the clonogenic cells expressing high levels of thioredoxin. In addition, there was differential sensitivity of the leukemia clonogenic cells toward 1-methylpropyl 2-imidazolyl disulfide, an inhibitor of thioredoxin expression, as compared with normal hematopoietic progenitors. This suggests the possibility of using this approach for treatment. Because overexpression of thioredoxin is associated with resistance to many anticancer drugs, the inhibition of thioredoxin expression may overcome this drug resistance and probably sensitize leukemia cells to other chemotherapeutic agents.

Expression of activin A in inflammatory arthropathies.

The findings that bone marrow fibroblastoid stromal cells are important for activin A production prompted our investigation of activin A expression in fibroblast-like synoviocytes in joint capsule in this and previous studies. In the proliferative reactive synovial membrane obtained from rheumatoid arthritis patients, activin A is detected prominently in the fibroblastoid synovial cells, as well as in the smooth muscle and the endothelial layer of the arteries in these vascularized proliferative tissues. The concentration of activin A in the rheumatoid arthritis synovial fluid was 33.6+/-5.0 ng/ml, much higher than the activin A content of osteoarthritis fluid (10.0+/-1.1 ng/ml). Furthermore, our previous studies also showed that inflammatory cytokines, such as interleukin (IL)-1, transforming growth factor (TGF)-beta, interferon (IFN)-gamma, IL-8, and IL-10 markedly enhance the expression of activin A mRNA in synoviocytes. These findings are consistent with our studies in regard to the regulatory control of activin A production in bone marrow stroma and monocytes. In addition, the relationship of activin A to IL-6-induced biological activities in various cell types was also investigated. Although activin A has not been directly associated with inflammatory processes, future studies are needed to investigate its production in response to the accumulated levels of inflammatory cytokines in the synovium of the patients, as well as the quantitative differences in activin A concentrations in many patients with other inflammatory diseases.