Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells.
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.
Sterneck
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Eukaryotic Transcriptional Regulation Group, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Kaplan
D R
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Johnson
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PF
D000310:Adrenal Gland Neoplasms; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005136:Eye Proteins / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects*; D015850:Interleukin-6 / Q000494:pharmacology*; D007381:Intermediate Filament Proteins / Q000096:biosynthesis*; D008222:Lymphokines / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology*; D009479:Neuropeptides / Q000096:biosynthesis; D016716:PC12 Cells; D064531:Peripherins; D010673:Pheochromocytoma; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020917:Receptor, trkA; D018123:Receptors, Interleukin / Q000096:biosynthesis; D019947:Receptors, Interleukin-6; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015703:Antigens, CD; D016228:Endothelial Growth Factors; D005136:Eye Proteins; D015850:Interleukin-6; D007381:Intermediate Filament Proteins; D008222:Lymphokines; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D064531:Peripherins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D017475:Receptors, Nerve Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019000:Phosphotyrosine; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases