Human myeloma cells shed the interleukin-6 receptor: inhibition by tissue inhibitor of metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor.
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.
Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School.
P G
PG
Hargreaves
F
F
Wang
J
J
Antcliff
G
G
Murphy
J
J
Lawry
R G
RG
Russell
P I
PI
Croucher
D001854:Bone Marrow Cells / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011480:Protease Inhibitors; D019947:Receptors, Interleukin-6; D013876:Thiophenes; D019717:Tissue Inhibitor of Metalloproteinase-3; D010649:Phenylalanine; C080985:batimastat; D013755:Tetradecanoylphorbol Acetate