Open Access

ARTICLE

Delineation of the roles of paracrine and autocrine interleukin-6 (IL-6) in myeloma cell lines in survival versus cell cycle. A possible model for the cooperation of myeloma cell growth factors

Michel Jourdan¹, Karène Mahtouk¹, Jean-luc Veyrune², Guilhem Couderc², Geneviève Fiol², Nicole Redal², Christophe Duperray¹, John De Vos^1,2, Bernard Klein^1,2

1 INSERM U475, 99 rue Puech Villa, 34197 Montpellier Cedex 5, France
2 Unit for Cellular Therapy, CHU Montpellier, Montpellier, France

* Corresponding Author: B. Klein,

European Cytokine Network 2005, 16(1), 57-64.

Abstract

Primary myeloma cells rapidly apoptose as soon as they are removed from their bone-marrow environment. A likely explanation is that the tumor environment produces survival factors that may counteract a spontaneous activation of pro-apoptotic program. Additional factors may trigger cell cycling in surviving myeloma cells. Interleukin-6 (IL-6) is a well recognized myeloma cell growth factor produced mainly by the tumor environment. However, myeloma cells themselves may produce low levels of autocrine IL-6. The respective roles of paracrine versus autocrine IL-6 are a matter of debate. We investigated these roles using the XG-6 myeloma cell line whose growth is dependent on addition of exogenous IL-6, despite its weak IL-6 mRNA and protein expression. The apoptosis induced by exogenous IL-6 deprivation was blocked by transferring the Mcl-1 gene coding for an anti-apoptotic protein in XG-6 cells. An XG-6Mcl-1 cell line which can survive and grow without adding IL-6 was obtained. We show that anti-IL-6 or anti-gp130 antibodies abrogated cell cycling whereas they did not affect cell survival. These data indicate that the weak autocrine IL-6 produced by myeloma cells is sufficient to trigger cell cycling whereas their survival requires large exogenous IL-6 concentrations. This important role of autocrine IL-6 has to be considered when evaluating the mechanism of action of myeloma cell growth factors. These factors may actually block an activated pro-apoptotic program, making possible a weak production of autocrine IL-6 to promote cell cycling.

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Keywords

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