Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells

J Neurochem. 1996 Oct;67(4):1365-74. doi: 10.1046/j.1471-4159.1996.67041365.x.


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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenal Gland Neoplasms
  • Animals
  • Antigens, CD / biosynthesis
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Differentiation / drug effects
  • Drug Synergism
  • Endothelial Growth Factors / biosynthesis
  • Eye Proteins / biosynthesis*
  • Gene Expression / drug effects*
  • Interleukin-6 / pharmacology*
  • Intermediate Filament Proteins / biosynthesis*
  • Lymphokines / biosynthesis
  • Membrane Glycoproteins*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Nerve Growth Factors / pharmacology*
  • Nerve Tissue Proteins*
  • Neurons / cytology*
  • Neuropeptides / biosynthesis
  • PC12 Cells
  • Peripherins
  • Pheochromocytoma
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / physiology*
  • RNA, Messenger / biosynthesis
  • Rats
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptor, trkA
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin-6
  • Receptors, Nerve Growth Factor / physiology*
  • Signal Transduction*
  • Transcription, Genetic
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Antigens, CD
  • Endothelial Growth Factors
  • Eye Proteins
  • Interleukin-6
  • Intermediate Filament Proteins
  • Lymphokines
  • Membrane Glycoproteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neuropeptides
  • Peripherins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-6
  • Receptors, Nerve Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Phosphotyrosine
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases