Induction of Neurite Outgrowth by Interleukin-6 Is Accompanied by Activation of Stat3 Signaling Pathway in a Variant PC12 Cell (E2) Line
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PC12-E2 cells, a stable variant subcloned from native cell populations, produce neurites in a rapid, transcription-independent manner upon exposure to nerve growth factor (NGF) or basic fibroblast growth factor (bFGF). They also give a similar morphological response to interleukin-6 (IL-6), which is, however, transcription-dependent and with a slower onset, a phenomenon basically not observed in native PC12 cells. The response profile of PC12-E2 cells to NGF and bFGF is similar to that observed for native PC12 cells pre-exposed (primed) to NGF, and such cells also respond to IL-6 in a fashion indistinguishable from PC12-E2 cells. Mechanistically, NGF and bFGF induce a sustained phosphorylation and activation of ERK1 and ERK2 in both cells, while IL-6 produces only a transient and weak tyrosine phosphorylation. However, it does stimulate a prolonged and biphasic tyrosine phosphorylation and nuclear translocation of Stat3 (signal transducers and activators of transcription 3; at least 24 h) and, to a lesser extent, Stat1. Gel shift and supershift analyses confirm that IL-6 predominantly activates Stat3 (and some Stat1) and stimulates sis-inducible element binding activity. Other members of the same cytokine subfamily, including ciliary neurotrophic factor and leukemia inhibitory factor, also cause a transient initial phase of tyrosine phosphorylation and activation of Stat1 and Stat3 (up to 1 h) but fail to stimulate a second phase of response and do not produce significant neurites. These results suggest that sustained signaling of either STAT or ERK pathways in PC12-E2 cells leads to induction of neuronal differentiation. However, only the latter is effective in native PC12 cells as the activation of Stat3 and Stat1 in native PC12 cells by IL-6 fails to induce neuronal differentiation. Thus, the response of PC12-E2 cells to IL-6 suggests the constitutive expression of a required factor(s) for differentiation, that is induced in native PC12 cells by NGF or bFGF (possibly by ERK activation), but not by IL-6 via Janus kinase/STAT activation. This factor(s), which has a sufficient half-life to allow primed cells to remain responsive to IL-6 for several days, is necessary but not sufficient for differentiation (as measured by neurite proliferation) to occur.
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Bi-phasic STAT3 activation has been reported in response to a variety of stimuli, including G-CSF, LIF, IL-6, and LPS.
“Bi-phasic STAT3 activation has been reported in response to a variety of stimuli, including granulocyte-colony stimulating factor (37), leukemia inhibitory factor (38), IL-6 (27,38), and lipopolysaccharide (39).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [38]
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- Authors
- Wu, Y. Y., & Bradshaw, R. A.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Bradshaw, Ralph A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-05
- Volume
- 271
- Issue
- 22
- Pages
- 13023-13032
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2092217194
- Cited by
- 100
- References
- 62
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2021: 1 · 2020: 1 · 2017: 4 · 2014: 4 · 2013: 5 · 2012: 3
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag009735-18)
- National Institute on Aging (AG-09735)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- interleukin-6, STAT3 signaling, STAT1, ERK1/2 activation, neuronal differentiation, neurite outgrowth, nerve growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, leukemia inhibitory factor, Janus kinase, tyrosine phosphorylation, signaling crosstalk
- MeSH terms
- Acute-Phase Proteins, Animals, Base Sequence, Cell Nucleus, DNA, DNA-Binding Proteins, Fibroblast Growth Factors, Humans, Kinetics, Molecular Sequence Data, Nerve Growth Factors, Phosphorylation, Protein Binding, Protein Kinases, Tyrosine, Signal Transduction, Trans-Activators, Interleukin-6, Neurites, PC12 Cells, STAT1 Transcription Factor, STAT3 Transcription Factor, Rats
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