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 Jourdan (1) , Karène Mahtouk (1) , Jean-Luc Veyrune (2) , Guilhem Couderc (2) , Geneviève Fiol (2) , Nicole Redal (2) , Christophe Duperray (1) , John de Vos (1, 2) , Bernard Klein (1, 2)

1 Immunopathologie des maladies tumorales et autoimmunes
2 Unité de thérapie cellulaire

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.

Mots clés: myeloma; IL-6; apoptosis; cell cycle

Domaines: Biochimie, Biologie Moléculaire

Michel Jourdan, Karène Mahtouk, Jean-Luc Veyrune, Guilhem Couderc, Geneviève Fiol, et al.. 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.. European Cytokine Network, 2005, 16 (1), pp.57-64. ⟨inserm-00130868⟩