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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Antigens, CD / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Cell Division / drug effects
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Cytokine Receptor gp130
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DNA-Binding Proteins / metabolism
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Fungal Proteins / metabolism
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Humans
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Interleukin-6 / pharmacology*
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JNK Mitogen-Activated Protein Kinases
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Janus Kinase 1
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Janus Kinase 2
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Membrane Glycoproteins / metabolism
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Multiple Myeloma / pathology*
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Neoplasm Proteins / physiology*
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Oligonucleotides, Antisense / pharmacology
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Protein Kinases / physiology*
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins*
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Repressor Proteins / metabolism
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SOS1 Protein
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STAT1 Transcription Factor
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STAT2 Transcription Factor
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Shc Signaling Adaptor Proteins
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Src Homology 2 Domain-Containing, Transforming Protein 1
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TYK2 Kinase
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Trans-Activators / metabolism
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Tumor Cells, Cultured / drug effects
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p38 Mitogen-Activated Protein Kinases
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ras Proteins / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, CD
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DNA-Binding Proteins
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Fungal Proteins
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IL6ST protein, human
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Interleukin-6
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Membrane Glycoproteins
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Neoplasm Proteins
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Oligonucleotides, Antisense
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Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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SHC1 protein, human
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SOS1 Protein
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT2 Transcription Factor
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Shc Signaling Adaptor Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Trans-Activators
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Cytokine Receptor gp130
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Protein Kinases
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK2 protein, human
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Janus Kinase 1
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Janus Kinase 2
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TYK2 Kinase
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TYK2 protein, human
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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ras Proteins