title: 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.
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.
authors.affiliation: INSERM U475, 99 rue Puech Villa, 34197 Montpellier Cedex 5, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Jourdan
authors.forename: Karène
authors.initials: K
authors.lastname: Mahtouk
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Veyrune
authors.forename: Guilhem
authors.initials: G
authors.lastname: Couderc
authors.forename: Geneviève
authors.initials: G
authors.lastname: Fiol
authors.forename: Nicole
authors.initials: N
authors.lastname: Redal
authors.forename: Christophe
authors.initials: C
authors.lastname: Duperray
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D019898:Autocrine Communication; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2