Inorganic polyphosphate and specific induction of apoptosis in human plasma cells

Abstract

BACKGROUND AND OBJECTIVES: Inorganic polyphosphate (polyP), a ubiquitous phosphate polymer with ATP-like bonds, has recently been related to a variety of functions including blood coagulation and cell proliferation. We investigated the effects of polyP in the biology of human plasma cells (PC), responsible for the production and maintenance of antibodies in response to antigens. DESIGN AND METHODS: The U266 myeloma cell line was used to study whether polyP affects immunoglobulin (Ig) secretion and survival. Different human cell lines were used to test the specificity of polyP on viability. We analyzed Ig secretion of PC from bone marrow and peripheral blood after polyP addition. A conventional tetanus toxoid booster immunization was used to increase the proportion of PC in order to examine the ex vivo effects of polyP. We also tested the effects of polyP on primary myeloma cells. Ig secretion and apoptosis were determined by ELISA and FACS respectively. RESULTS: Addition of polyP to human PC produced an unexpected inhibition of Ig secretion and stimulation of apoptosis. PolyP generated apoptosis specifically in PC, myeloma (malignant PC) cell lines, primary myeloma cells, and B lymphoid cell lines. Normal B cells, T cells, total blood mononuclear cells, and non-lymphoid cell lines were not affected by polyP. In the U266 myeloma cell line, polyP induced externalization of phosphatidylserine, activation of caspase-3, and arrest of the cell cycle. The protective effects of interleukin-6 did not overcome the polyP-induced apoptosis Interpretation and CONCLUSIONS: Taken together, our results suggest for the first time the relevance of the use of polyP to the humoral immune response and open prospects for polyP as a novel therapy for myeloma.