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) 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.
Torcia
M
M
Department of Experimental Medicine, University of Roma Tor Vergata, Italy.
Lucibello
M
M
Vannier
E
E
Fabiani
S
S
Miliani
A
A
Guidi
G
G
Spada
O
O
Dower
S K
SK
Sims
J E
JE
Shaw
A R
AR
Dinarello
C A
CA
Garaci
E
E
Cozzolino
F
F
D000818:Animals; D000911:Antibodies, Monoclonal; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D001854:Bone Marrow Cells; D001862:Bone Resorption; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology*; D008222:Lymphokines / Q000276:immunology / Q000502:physiology*; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D009101:Multiple Myeloma / Q000473:pathology*; D009367:Neoplasm Staging; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008222:Lymphokines; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; C008718:osteoclast activating factor; D002118:Calcium