INTERLEUKIN-2 INCREASES PRODUCTION AND SECRETION OF PARATHYROID HORMONE-RELATED PEPTIDE BY HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I-INFECTED T-CELLS - POSSIBLE ROLE IN HYPERCALCEMIA ASSOCIATED WITH ADULT T-CELL LEUKEMIA

Although parathyroid hormone-related peptide (PTHRP) is produced by ad ult T cell leukemia (ATL) cells and causes hypercalcemia in ATL patien ts, very little is known about the regulation of PTHRP gene expression in the leukemic cells. The present study was undertaken to clarify th e role of T cell growth factor, interleukin-2 (IL-2), in the expressio n of PTHRP gene, using a human T cell leukemia virus type I (HTLV-I)-i nfected T cell line, MT-2. Recombinant human IL-2 caused a transient i ncrease in the steady state level of PTHRP messenger RNA (mRNA) in MT- 2 cells, and a maximal effect was observed at 3-6 h. The effect of IL- 2 was dose dependent, with a maximal response being observed at 10(-10 ) M. A monoclonal antibody against IL-2 receptor (anti-Tac antibody) i nhibited the IL-2-induced increase in PTHRP mRNA level. Recombinant hu man IL-1, IL-3, IL-4, and IL-6 failed to increase PTHRP mRNA level. Nu clear run-off transcription assay showed that the transcription rate o f the PTHRP gene was modestly increased by IL-2. In addition, IL-2 cau sed a substantial increase in the stability of PTHRP mRNA, compared wi th control cells in which the apparent half-life of PTHRP mRNA was les s than 30 min after RNA synthesis was inhibited by the RNA polymerase II inhibitor, dichlorobenzimidazole riboside. The secretion of PTHRP, as determined by both a newly established immunoradiometric assay usin g recombinant human PTHRP(1-87) as the standard and an RIA using an an tibody against PTHRP(109-141), was increased by IL-2 but not by IL-1, IL-3, IL-4, or IL-6. The IL-2-induced increase in PTHRP secretion was completely inhibited by the addition of anti-Tac antibody. These resul ts demonstrate that IL-2 stimulates the production and secretion of PT HRP by HTLV-I-infected T cells through specific binding to IL-2 recept or and that the effect of IL-2 is mediated by a posttranscriptional as well as a transcriptional mechanism. It is suggested that IL-2 may be involved in an auctocrine/paracrine fashion not only in the prolifera tion of HTLV-I-infected T cells but also in the enhanced production an d secretion of PTHRP and thus the development of hypercalcemia in ATL patients.