Abstract
In contrast to the intensively studied nerve growth factor (NGF)-related family of cytokines, relatively little is known about the mechanisms of neurotrophic activity elicited by the cytokine interleukin-6 (IL-6). We have examined the mechanisms of IL-6-induced neuronal differentiation of the pheochromocytoma cell line PC12. IL-6 independently induced the expression of peripherin, identifying this gene as the first neuronal-specific target of IL-6. However, IL-6 alone failed to elicit neurite outgrowth in PC12 cells and instead required low levels of Trk/NGF receptor tyrosine kinase activity to induce neuronal differentiation. The cooperating Trk signal could be provided by either overexpression of Trk or exposure to low concentrations of NGF. IL-6 also functioned cooperatively with basic fibroblast growth factor to promote PC12 differentiation. IL-6 and Trk/NGF synergized in enhancing tyrosine phosphorylation of the Erk-1 mitogen-activated protein kinase and in activating expression of certain NGF target genes. NGF also induced expression of the gp80 subunit of the IL-6 receptor, providing another potential mechanism of cooperativity between NGF and IL-6 signaling. We propose that IL-6 functions as an enhancer of NGF signaling rather than as an autonomous neuronal differentiation signal. Moreover, our results demonstrate that a Trk receptor-specific cellular response can be achieved in the absence of NGF through amplification of its basal signaling activity by the IL-6 receptor system.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenal Gland Neoplasms
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Animals
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Antigens, CD / biosynthesis
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Differentiation / drug effects
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Drug Synergism
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Endothelial Growth Factors / biosynthesis
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Eye Proteins / biosynthesis*
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Gene Expression / drug effects*
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Interleukin-6 / pharmacology*
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Intermediate Filament Proteins / biosynthesis*
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Lymphokines / biosynthesis
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Membrane Glycoproteins*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Nerve Growth Factors / pharmacology*
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Nerve Tissue Proteins*
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Neurons / cytology*
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Neuropeptides / biosynthesis
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PC12 Cells
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Peripherins
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Pheochromocytoma
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Phosphorylation
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Phosphotyrosine / metabolism
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Polymerase Chain Reaction
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Proto-Oncogene Proteins / physiology*
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RNA, Messenger / biosynthesis
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Rats
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Receptor Protein-Tyrosine Kinases / physiology*
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Receptor, trkA
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin-6
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Receptors, Nerve Growth Factor / physiology*
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Signal Transduction*
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Transcription, Genetic
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Antigens, CD
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Endothelial Growth Factors
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Eye Proteins
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Interleukin-6
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Intermediate Filament Proteins
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Lymphokines
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Membrane Glycoproteins
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Nerve Growth Factors
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Nerve Tissue Proteins
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Neuropeptides
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Peripherins
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-6
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Receptors, Nerve Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Phosphotyrosine
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Receptor Protein-Tyrosine Kinases
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Receptor, trkA
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases