Mechanism and regulation of hypercalcemia in adult T-cell leukemia

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We have proposed that highly associated hypercalcemia in adult T-cell leukemia (ATL) may be induced by synergetic effects of interleukin-1 production through a vicious cycle and PTHrP production from ATL cells.In this study, the new following findings were obtained in ATL.1. PTHrP production, mRNA expression and the growth of ATL cells were rather enhanced in cell culture system under abnormally high levels of calcium condition (up to 4mM) suggesting that there may be another vicious cycle in hypercalcemia of ALT.2. IL-2 increased PTHrP production in culture nedia. In contrast, IL-4 which is known to be one of bone resorption inhibiting factor decreased mRNA expression of potent bone resorption stimulating factor (BRSF), IL-6, suggesting that various kind of cytokines may be involved in enhancement or inhibition of hypercalcemia of ATL.3. It was demonstrated that osteoblastic cells adhered to ATL cells, and ATL cells adhered homotypically througha the expression of various kinds of cellular adhesion molecles on the cell surface. Subsequently, these cellular adhesion induced the production of IL-1 and IL-6, very potent BRSF,suggesting that cell-cell adhesion may be involved in the induction of hypercalcemia in ATL as an additional important key.4. The proliferation of ATL cells and PTHrP production from ATL cells were inhibited by an analog of V.D3 (OCT). Also, it was confirmed that IL-4 inhibited hypercalcemia and decreased the number of osteoclasts in in-vivo experiment. These results suggest that OCT and IL-4 may be usuful candidates for the inhibition of malignant hypercalcemia.