MODULATION OF OSTEOCLAST-ACTIVATING FACTOR ACTIVITY OF MULTIPLE-MYELOMA BONE-MARROW CELLS BY DIFFERENT INTERLEUKIN-1 INHIBITORS

We have studied the effects of several interleukin-1 (IL-1) inhibitors -IL-1 receptor antagonist (IL-1ra), soluble IL-1 receptor (sIL-1R) typ es I and II, and neutralizing monoclonal antibody (mAb) specific for I L-1 receptor type I-on the osteoclast-activating factor (OAF) activity of recombinant IL-1 beta and of culture supernatants of unfractionate d bone marrow mononuclear cells from multiple myeloma (MM) patients. T he latter activity sharply correlated with the IL-1 content of culture supernatants (r = 0.949; p < 0.001). IL-1ra and sIL-1R types I and II had a clear-cut modulating effect on the OAF activity of IL-beta at s aturating doses (2-10 ng/mL); their effect was evident at 2 ng/mL and was dose-dependent over a large range of concentrations. Similarly, th e three reagents neutralized the OAF activities of all MM cell superna tants in a dose-dependent fashion and completely abolished them when t ested at the fixed concentration of 5 nM. The bone-resorbing activity of tumor necrosis factor-alpha (TNF-alpha) or lymphotoxin (LT), tested alone or added to MM cell supernatants, was affected not at all by IL -1ra and only minimally by sIL-1R types I and II, suggesting that litt le or no endogenous IL-1 was produced by the rat cells in the assay un der TNF-alpha or LT stimulation. Consistent with these findings, PGE, production elicited by IL-1 beta or IL-1-rich supernatants in the rat long-bone assay was abolished by each reagent. Also, mAbs to the IL-1R p80 (type I) chains could modulate the effects of IL-1-recombinant or plasma cell-derived-in the OAF assay, but their activity was markedly less pronounced when compared with the IL-1 inhibitors, since they co uld never completely abolish bone resorption. Taken together, these fi ndings demonstrate that inhibition of IL-1 interaction with cognate su rface receptors on bone cells effectively counteracts its biologic act ivity. The findings also strongly indicate that OAF activity in condit ioned medium of unfractionated myeloma bone marrow cells is predominan tly, if not solely, related to IL-1 beta.