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MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis
A Kotlyarov1, A Neininger, C Schubert
1Martin-Luther-University Halle-Wittenberg, Germany.
Abstract:
MAPKAP kinase 2 (MK2) is one of several kinases that are regulated through direct phosphorylation by p38 MAP kinase. By introducing a targeted mutation into the mouse MK2 gene, we have determined the physiological function of MK2 in vivo. Mice that lack MK2 show increased stress resistance and survive LPS-induced endotoxic shock. This is due to a reduction of approximately 90% in the production of tumor necrosis factor-alpha (TNF-alpha) and not to a change in signalling from the TNF receptor. The level and stability of TNF-alpha mRNA is not reduced and TNF-alpha secretion is not affected. We conclude that MK2 is an essential component in the inflammatory response which regulates biosynthesis of TNF-alpha at a post-transcriptional level.
Insights
MAPKAP kinase 2 (MK2) regulates tumor necrosis factor-alpha (TNF-alpha) biosynthesis. MK2-deficient mice exhibit enhanced stress resistance and survival during endotoxic shock due to reduced TNF-alpha production.
Area of Science:
- Molecular Biology
- Immunology
- Cell Signaling
Background:
- MAPKAP kinase 2 (MK2) is phosphorylated by p38 MAP kinase.
- The physiological role of MK2 in vivo remains largely uncharacterized.
Purpose of the Study:
- To elucidate the in vivo function of MK2.
- To investigate MK2's role in the inflammatory response and endotoxic shock.
Main Methods:
- Targeted gene mutation to create MK2-deficient mice.
- Assessment of stress resistance and survival following LPS-induced endotoxic shock.
- Quantification of TNF-alpha production and analysis of TNF-alpha mRNA stability.
Main Results:
- MK2-deficient mice displayed increased stress resistance.
- Survival rates were significantly higher in MK2-deficient mice during LPS-induced endotoxic shock.
- A ~90% reduction in TNF-alpha production was observed in MK2-deficient mice, independent of TNF receptor signaling.
Conclusions:
- MK2 is crucial for the inflammatory response.
- MK2 regulates TNF-alpha biosynthesis at a post-transcriptional level.
- MK2 deficiency confers protection against endotoxic shock by limiting TNF-alpha production.