Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium

Interleukin-6 (IL-6) is known to enhance osteoclast recruitment, and thereby bone resorption, Thus, IL-6 has been proposed to mediate hypercalcemia in multiple myeloma and the enhanced osteoclastic activity seen in postmenopausal osteoporosis, We recently reported that the calcium concentration in plasma affects IL-6 secretion from mononuclear blood cells, To investigate the underlying mechanism, we have studied the effect of calcium on IL-6 formation in mononuclear blood cells ex vivo and in vitro. Thirteen healthy volunteers were given 1 g of calcium orally after overnight fasting, Plasma levels of ionized calcium (pCa(2+)) and serum levels of parathyroid hormone (sPTH) were measured after 2 and 4 h, with all subjects still fasting, After 2 h, pCa(2+) was increased and sPTH decreased in all 13 persons, IL-6 secretion ex vivo from mononuclear blood cells drawn 4 h after calcium intake was increased 185% as compared with IL-6 secretion from cells drawn just before calcium intake, In control experiments without calcium intake, there was no alteration in pCa(2+) and no effect on IL-6 secretion from mononuclear blood cells, In vitro studies revealed that stimulation of isolated mononuclear blood cells with physiological concentrations of calcium dose-dependently increased IL-6 secretion with an estimated EC(50) at 1.2 mM Ca2+. No effect on the IL-6 secretion was seen following treatment of the isolated mononuclear blood cells with PTH or calcitonin, These observations demonstrate that the plasma calcium concentration affects IL-6 secretion from mononuclear blood cells, The in vitro data indicate the involvement of a direct calcium sensing mechanism. These findings might have implications in hypercalcemia and should also be borne in mind when considering the role of cytokines in osteoporosis.