Modulation of osteoclast-activating factor activity of multiple myeloma bone marrow cells by different interleukin-1 inhibitors

M. Torcia, M. Lucibello, E. Vannier, S. Fabiani, A. Miliani, G. Guidi, O. Spada, S. K. Dower, J. E. Sims, A. R. Shaw, C. A. Dinarello, E. Garaci, F. Cozzolino

Research output: Contribution to journalArticle

Abstract

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-1β 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-1β 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-α (TNF-α) 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-α or LT stimulation. Consistent with these findings, PGE2 production elicited by IL-1β 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-1β.

Original languageEnglish
Pages (from-to)868-874
Number of pages7
JournalExperimental Hematology
Volume24
Issue number8
Publication statusPublished - 1996

Keywords

  • IL-1 inhibitor
  • Multiple myeloma
  • OAF

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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  • Cite this

    Torcia, M., Lucibello, M., Vannier, E., Fabiani, S., Miliani, A., Guidi, G., Spada, O., Dower, S. K., Sims, J. E., Shaw, A. R., Dinarello, C. A., Garaci, E., & Cozzolino, F. (1996). Modulation of osteoclast-activating factor activity of multiple myeloma bone marrow cells by different interleukin-1 inhibitors. Experimental Hematology, 24(8), 868-874.