Interleukin-4 (IL-4) is an immune cytokine recently shown to inhibit bone resorption. To determine whether IL-4 directly acts on osteoclasts, we have analyzed its effect on cytosolic calcium concentration [Ca2+](i) and bone resorptive function of murine osteoclastic cells generated from bone marrow/stromal cell co-cultures. IL-4 exposure induced an immediate and sustained increase in [Ca2+](i) that remained elevated for at least 10 min. This IL-4 effect was dose-dependent, with the maximal effect (209 ± 15% of baseline, n = 16) at 200 units/ml and an apparent ED0.5 of 60 units/ml. The IL-4-induced [Ca2+], rise required extracellular Ca2+ influx, since the response was prevented by LaCl3, and voltage-gated Ca2+ channel blockers, although the IL-4 effect was more sensitive to nicardipine and nifedipine than to diltiazem. Depolarization by high extracellular K+ concentration also raised [Ca2+](i), and, under these conditions, osteoclasts failed to respond to IL-4. On the other hand, when intracellular Ca2+ stores were depleted by thapsigargin. IL-4 still induced an increase in [Ca2+](i), although smaller in amplitude and transient. Calcitonin also produced [Ca2+](i) increases in osteoclasts, yet it only slightly desensitized these cells to IL-4. Furthermore, IL-4 was much less effective on osteoclasts pretreated (5-10 min) with either forskolin or 8-bromo-cAMP. Both IL-4 and calcitonin were effective even when [Ca2+](i) had been increased by exposure to high extracellular Ca2+. Finally, IL-4 dose dependently inhibited the bone-resorptive activity of mature osteoclasts. Therefore, IL-4 signal transduction in osteoclasts involves a rapid and sustained elevation of [Ca2+](i) mediated by a voltage-dependent Ca2+ influx, in combination with Ca2+ release from intracellular stores. Modulation of osteoclast [Ca2+](i) represents a potential mechanism by which IL-4 inhibits bone resorption.

Original languageEnglish
Pages (from-to)13817-13824
Number of pages8
JournalJournal of Biological Chemistry
Issue number19
StatePublished - 1994


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