INTERLEUKIN-4, INTERFERON-GAMMA, AND PROSTAGLANDIN-E IMPACT THE OSTEOCLASTIC CELL-FORMING POTENTIAL OF MURINE BONE-MARROW MACROPHAGES

Interleukin 4 (IL-4) is an immune cytokine that inhibits bone resorpti on in mice and suppresses osteoclastic cell formation in vitro through an undefined mechanism. In this report, we have established the cellu lar identity of the IL-4 target cell using a variety of bone marrow/st romal cell coculture methods. Initially, we found that the majority of IL-4's inhibition of osteoclastic cell formation was due to its effec t on bone marrow cells, not stromal cells. Consequently, bone marrow m acrophages were used as osteoclastic cell progenitors after they had b een transiently exposed to IL-4 (48 h), before the addition of stromal cells, 1,25-dihydroxyvitamin D-3, and dexamethasone. In this circumst ance, IL-4 impaired subsequent osteoclastic cell formation, suggesting that the macrophage may be potentially targeted by many factors known to influence osteoclast formation. Consequently, we discovered that i nterferon-gamma (IFN gamma), prostaglandin E (PGE), and cell-permeant cAMP analogs also impacted osteoclastic cell formation when used to se lectively treat bone marrow macrophages. IFN gamma suppressed osteocla stic cell formation, whereas PGE and cAMP analog treatment led to the formation of significantly enlarged osteoclastic cells. Importantly, P GE antagonized the inhibitory effects of both IL-4 and IFN gamma on th e osteoclastic cell-forming potential of bone marrow macrophages. Coll ectively, these findings establish bone marrow macrophages as osteocla stic cell precursors with the degree of their commitment to the osteoc last pathway sensitive to the effects of soluble mediators, including IL-4, IFN gamma, and PGE.