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LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages
J G Bode1, A Nimmesgern, J Schmitz
1Institut für Biochemie, Klinikum der RWTH Aachen, Pauwelsstrasse 30, 52057, Aachen, Germany.
Abstract:
Recent findings indicate that cytokine signaling can be modulated by other mediators of simultaneously activated signal transduction pathways. In this study we show that LPS and TNFalpha are potent inhibitors of IL-6-mediated STAT3 activation in human monocyte derived macrophages, rat liver macrophages and RAW 264.7 mouse macrophages but not in human hepatoma cells (HepG2) or in rat hepatocytes. Accordingly, LPS and TNFalpha were found to induce the expression of SOCS3 mRNA in each of the investigated type of macrophages but not in HepG2 cells. Using a specific inhibitor, evidence is presented that the p38 MAP kinase might be involved, especially for the inhibitory effect of TNFalpha.
Insights
Lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNFα) inhibit interleukin-6 (IL-6)-mediated STAT3 activation in macrophages. This inhibition is linked to increased SOCS3 mRNA expression, potentially involving p38 MAP kinase.
Area of Science:
- Immunology
- Cellular Signaling
- Molecular Biology
Background:
- Cytokine signaling pathways are crucial in immune responses.
- These pathways can be modulated by other signaling mediators.
- Understanding these interactions is key to controlling inflammatory processes.
Purpose of the Study:
- To investigate the inhibitory effects of lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNFα) on interleukin-6 (IL-6)-mediated signal transducer and activator of transcription 3 (STAT3) activation.
- To determine the cell-type specificity of this inhibition.
- To explore the role of Suppressors of Cytokine Signaling 3 (SOCS3) and p38 MAP kinase in this regulatory mechanism.
Main Methods:
- Utilized human monocyte-derived macrophages, rat liver macrophages, RAW 264.7 mouse macrophages, HepG2 cells, and rat hepatocytes.
- Administered LPS and TNFα to modulate cytokine signaling.
- Measured STAT3 activation and SOCS3 mRNA expression.
- Employed a specific p38 MAP kinase inhibitor.
Main Results:
- LPS and TNFα potently inhibited IL-6-mediated STAT3 activation in all tested macrophage types but not in HepG2 cells or rat hepatocytes.
- Both LPS and TNFα induced SOCS3 mRNA expression in macrophages, but not in HepG2 cells.
- Evidence suggests p38 MAP kinase involvement, particularly in TNFα's inhibitory effect.
Conclusions:
- Macrophages exhibit a distinct response to LPS and TNFα regarding IL-6/STAT3 signaling compared to liver cells.
- SOCS3 induction is a key mechanism mediating the inhibitory effects of LPS and TNFα on STAT3 activation in macrophages.
- The p38 MAP kinase pathway is implicated in the TNFα-mediated inhibition of IL-6 signaling.