Human myeloma cells shed the interleukin-6 receptor: inhibition by tissue inhibitor of metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor

Br J Haematol. 1998 Jun;101(4):694-702. doi: 10.1046/j.1365-2141.1998.00754.x.


Interleukin-6 (IL-6) is the major growth factor for human myeloma cells, exerting its effect through the IL-6 receptor (IL-6R). A soluble form of IL-6R (sIL-6R) has been identified, which increases the sensitivity of myeloma cells to IL-6. In patients with multiple myeloma (MM), serum concentrations of sIL-6R are elevated and associated with poor prognosis. The present study was undertaken to determine whether proteolytic cleavage of IL-6R could contribute to sIL-6R release from human myeloma cells, and also to identify the class of proteinase responsible for this event. Human myeloma cell lines were shown to express IL-6R upon their surface and also to release sIL-6R into culture supernatants. In addition, phorbol 12-myristate 13-acetate (PMA) stimulated a loss of IL-6R from the cell surface, with a corresponding increase in the concentration of sIL-6R in the supernatant. Inhibitors of serine and cysteine proteinases, and tissue inhibitor of metalloproteinase (TIMP) -1 and TIMP-2, were shown to have no effect on the magnitude of sIL-6R release. In contrast, TIMP-3 and a hydroxamate-based metalloproteinase inhibitor (BB-94), inhibited both constitutive and PMA-induced release of sIL-6R. Myeloma cells freshly isolated from the bone marrow of a patient with MM were also shown to express IL-6R upon their surface, and to shed this receptor in response to PMA. These data demonstrate that increased proteolytic cleavage of IL-6R, mediated by a non-matrix-type metalloproteinase, is likely to contribute to the elevated concentrations of sIL-6R found in the serum of patients with MM. Inhibition of sIL-6R release by hydroxamate-based metalloproteinase inhibitors may represent a novel therapeutic approach to the treatment of MM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow Cells / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Multiple Myeloma / metabolism*
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology
  • Protease Inhibitors / pharmacology
  • Receptors, Interleukin-6 / antagonists & inhibitors*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Thiophenes / pharmacology
  • Tissue Inhibitor of Metalloproteinase-3 / pharmacology*
  • Tumor Cells, Cultured


  • Protease Inhibitors
  • Receptors, Interleukin-6
  • Thiophenes
  • Tissue Inhibitor of Metalloproteinase-3
  • Phenylalanine
  • batimastat
  • Tetradecanoylphorbol Acetate