IL-6 TRIGGERS CELL-GROWTH VIA THE RAS-DEPENDENT MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE

IL-6 mediates growth of some human multiple myeloma (MM) cells and IL- 6-dependent cell lines, Although three IL-6 signaling pathways (STAT1, STAT3, and Ras-dependent MAPK cascade) have been reported, cascades m ediating IL-6-triggered growth of MM cells and cell lines are not defi ned. In this study, we therefore characterized IL-6 signaling cascades in MM cell lines, MM patient cells, and IL-6-dependent B9 cells to de termine which pathway mediates IL-6-dependent growth, IL-6 induced pho sphorylation of JAK kinases and gp130, regardless of the proliferative response of MM cells to this growth factor. Accordingly, we next exam ined downstream IL-6 signaling via the STAT3, STAT1, and pas-dependent mitogen-activated protein kinase (MAPK) cascades. IL-6 triggered phos phorylation of STAT1 and/or STAT3 in MM cells independent of their pro liferative response to IL-6. In contrast, IL-6 induced phosphorylation of She and its association with Sos1, as well as phosphorylation of M APK, only in MM cells and B9 cells that proliferated in response to IL -6. Moreover, MAPK antisense, but not sense, oligonucleotide inhibited IL-6-induced proliferation of these cells. These data suggest that ST AT1 and/or STAT3 activation may occur independently of the proliferati ve response to IL-6, and that activation of the MAPK cascade is an imp ortant distal pathway for IL-6-mediated growth.