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IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade
1Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
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 mediating IL-6-triggered growth of MM cells and cell lines are not defined. In this study, we therefore characterized IL-6 signaling cascades in MM cell lines, MM patient cells, and IL-6-dependent B9 cells to determine which pathway mediates IL-6-dependent growth. IL-6 induced phosphorylation of JAK kinases and gp130, regardless of the proliferative response of MM cells to this growth factor. Accordingly, we next examined downstream IL-6 signaling via the STAT3, STAT1, and Ras-dependent mitogen-activated protein kinase (MAPK) cascades. IL-6 triggered phosphorylation of STAT1 and/or STAT3 in MM cells independent of their proliferative response to IL-6. In contrast, IL-6 induced phosphorylation of Shc and its association with Sos1, as well as phosphorylation of MAPK, 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 STAT1 and/or STAT3 activation may occur independently of the proliferative response to IL-6, and that activation of the MAPK cascade is an important distal pathway for IL-6-mediated growth.
Insights
Interleukin-6 (IL-6) triggers multiple myeloma cell growth via the mitogen-activated protein kinase (MAPK) cascade. STAT1 and STAT3 activation by IL-6 occurs independently of this growth response.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Interleukin-6 (IL-6) is a key cytokine involved in the growth of human multiple myeloma (MM) cells.
- Several IL-6 signaling pathways, including STAT1, STAT3, and the Ras-dependent mitogen-activated protein kinase (MAPK) cascade, are known, but the specific pathways mediating MM cell growth are not fully defined.
Purpose of the Study:
- To investigate and define the IL-6 signaling cascades responsible for the growth of multiple myeloma cells.
- To differentiate between IL-6 signaling pathways that are activated independently of proliferation and those that mediate growth.
Main Methods:
- Characterization of IL-6 signaling pathways (STAT1, STAT3, MAPK) in MM cell lines, patient cells, and IL-6-dependent B9 cells.
- Assessment of protein phosphorylation (JAK kinases, gp130, STAT1, STAT3, Shc, MAPK) and protein-protein interactions (Shc-Sos1).
- Inhibition of IL-6-induced proliferation using MAPK antisense oligonucleotides.
Main Results:
- IL-6 induced phosphorylation of JAK kinases and gp130 in all tested MM cells, irrespective of their proliferative response.
- IL-6 triggered STAT1 and/or STAT3 phosphorylation in MM cells, also independent of proliferation.
- Activation of the MAPK cascade (Shc-Sos1 association and MAPK phosphorylation) was observed exclusively in IL-6-responsive MM cells and B9 cells.
- MAPK antisense oligonucleotides significantly inhibited IL-6-induced proliferation.
Conclusions:
- STAT1 and STAT3 activation by IL-6 can occur independently of the growth-promoting signaling cascade.
- The Ras-dependent MAPK cascade plays a crucial role as a distal signaling pathway mediating IL-6-induced proliferation in multiple myeloma cells.