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Myeloma Cells Release Soluble Interleukin-6R in Relation to Disease Progression by Two Distinct Mechanisms: Alternative Splicing and Proteolytic Cleavage¹

Institut National de la Santé et de la Recherche Médicale Unité 463 [W. T., S. B., M. C., R. B., M. A.], Institut de Biologie, and Département d’Hématologie Clinique [J-L. H., M-J. R.], 44093 Nantes cedex 01, France

Multiple myeloma (MM) is a plasma-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. Interleukin (IL)-6 is an essential survival and growth factor for myeloma cells that exerts its activity through a cell surface receptor composed of an 80-kDa ligand binding molecule (IL-6R) and a 130-kDa signal-transducing molecule. Of major interest, the soluble form of the IL-6R (sIL-6R) is an agonistic molecule able to potentiate IL-6 activity and a strong prognostic factor in MM. In the present study, we demonstrate that purified myeloma cells from all of the patients with MM and human myeloma cell lines release sIL-6R. The level of sIL-6R release correlates with disease activity and is clearly up-regulated during tumoral expansion in vivo and immortalization in vitro. Of note, this sIL-6R release is strongly reduced (50%) by a hydroxamate-based metalloproteinase inhibitor underlying the importance of shedding in the production of sIL-6R by myeloma cells. Using specific IL-6R primers flanking the transmembrane domain, we demonstrate by PCR the presence of two IL-6R mRNAs corresponding to the membrane IL-6R and to the sIL-6R generated through alternative splicing in myeloma cells. In conclusion, we show that: (a) native myeloma cells and human myeloma cell lines release sIL-6R by two distinct mechanisms: alternative splicing and proteolytic cleavage of the membrane IL-6R; and (b) the release of the sIL-6R, which is an agonist of IL-6, correlates with disease progression, explaining in part its strong prognostic value in vivo.

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