We have studied the effects of several
interleukin-1 (IL-1) inhibitors--IL-1 receptor antagonist (IL-1ra), soluble
IL-1 receptor (sIL-1R) types I and II, and neutralizing
monoclonal antibody (mAb) specific for
IL-1 receptor type I--on the
osteoclast-activating factor (OAF) activity of recombinant IL-1beta and of culture supernatants of unfractionated bone marrow mononuclear cells from
multiple myeloma (MM) patients. The 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-1beta at saturating doses (2-10 ng/mL); their effect was evident at 2 ng/mL and was dose-dependent over a large range of concentrations. Similarly, the three
reagents neutralized the OAF activities of all MM cell supernatants in a dose-dependent fashion and completely abolished them when tested 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 little or no endogenous
IL-1 was produced by the rat cells in the assay under
TNF-alpha or LT stimulation. Consistent with these findings,
PGE2 production elicited by IL-1beta 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 could never completely abolish
bone resorption. Taken together, these findings demonstrate that inhibition of
IL-1 interaction with cognate surface receptors on bone cells effectively counteracts its
biologic activity. The findings also strongly indicate that OAF activity in
conditioned medium of unfractionated myeloma bone marrow cells is predominantly, if not solely, related to IL-1beta.