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Induction of an interferon-gamma Stat3 response in nerve cells by pre-treatment with gp130 cytokines
Navjot Kaur1, In-Jung Kim, Dennis Higgins
1Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, New York 14214, USA.
Abstract:
Many cytokines mediate their effects through Jak/STAT signaling pathways providing many opportunities for cross-talk between different cytokines. We examined the interaction between two cytokine families, gp130-related cytokines and interferon-gamma (IFN-gamma), which are coexpressed in the nervous system during acute trauma and pathological conditions. Typical nerve cells show an IFN-gamma response that is restricted to activating STAT1, with minor activation of STAT3. IFN-gamma elicited a pronounced STAT3 response in cells pre-treated for 5-7 h with ciliary neurotrophic factor (CNTF), leukemia inhibitory factor or interleukin-6. CNTF or interleukin-6 induced an IFN-gamma STAT3 response in a variety of cells including SH-SY5Y human neuroblastoma, HMN-1 murine motor neuron hybrid cells, rat sympathetic neurons and human hepatoma HepG2 cells. The enhancement was measured as an increase in tyrosine phosphorylated STAT3, in STAT3-DNA binding and in STAT-luciferase reporter gene activity. The enhanced STAT3 response was not due to an increase in overall STAT3 levels but was dependent upon ongoing protein synthesis. The induction by CNTF was inhibited by the protein kinase C inhibitor, BIM, and the MAPK-kinase inhibitor, U0126. Further, H-35 hepatoma cells expressing gp130 receptor chimeras lacking either the SHP-2 docking site or the Box 3 STAT binding sites failed to enhance the IFN-gamma STAT3 response. These results provide evidence for an interaction between gp130 and IFN-gamma cytokines that can significantly alter the final cellular response to IFN-gamma.
Insights
Cytokine cross-talk between gp130-related cytokines and interferon-gamma (IFN-gamma) enhances STAT3 activation in nerve cells. This interaction, crucial in neurological conditions, involves protein synthesis and specific signaling pathways.
Area of Science:
- Neuroscience
- Immunology
- Cellular Biology
Background:
- Cytokines utilize Jak/STAT pathways, enabling cross-talk.
- gp130-related cytokines and IFN-gamma co-occur in the nervous system during trauma and disease.
Purpose of the Study:
- Investigate the interaction between gp130-related cytokines and IFN-gamma.
- Determine how this interaction affects STAT signaling in nerve cells.
Main Methods:
- Assessed STAT1 and STAT3 activation in response to IFN-gamma.
- Examined STAT3 activation after pre-treatment with CNTF, LIF, or IL-6.
- Utilized various cell types including neuroblastoma and motor neuron hybrid cells.
- Measured STAT3 phosphorylation, DNA binding, and reporter gene activity.
- Investigated the role of protein synthesis and specific signaling inhibitors (BIM, U0126).
- Employed gp130 receptor chimeras to identify critical signaling domains.
Main Results:
- IFN-gamma primarily activates STAT1, with minimal STAT3 activation in typical nerve cells.
- Pre-treatment with CNTF, LIF, or IL-6 significantly enhanced IFN-gamma-induced STAT3 activation.
- This enhancement was observed across multiple cell types, including neuronal and hepatoma cells.
- Increased STAT3 response was not due to elevated STAT3 levels but required protein synthesis.
- CNTF-induced enhancement was inhibited by PKC and MAPK pathway inhibitors.
- Specific gp130 receptor domains (SHP-2 docking, Box 3) were essential for the enhancement.
Conclusions:
- gp130-related cytokines modulate IFN-gamma signaling by enhancing STAT3 activation.
- This cross-talk mechanism is dependent on protein synthesis and specific intracellular signaling pathways.
- The findings reveal a significant interaction between these cytokine families that alters cellular responses to IFN-gamma.
