Abstract
BackgroundMAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. Among others, MK2 is known to be involved in the regulation of cytokine mRNA metabolism and regulation of actin cytoskeleton dynamics. Previously, MK2-deficient mice were shown to be highly resistant to LPS/d-Galactosamine-induced hepatitis. Additionally, research in various disease models has indicated the kinase as an interesting inhibitory drug target for various acute or chronic inflammatory diseases.ResultsWe show that in striking contrast to the known resistance of MK2-deficient mice to a challenge with LPS/D-Gal, a low dose of tumor necrosis factor (TNF) causes hyperacute mortality via an oxidative stress driven mechanism. We identified in vivo defects in the stress fiber response in endothelial cells, which could have resulted in reduced resistance of the endothelial barrier to deal with exposure to oxidative stress. In addition, MK2-deficient mice were found to be more sensitive to cecal ligation and puncture-induced sepsis.ConclusionsThe capacity of the endothelial barrier to deal with inflammatory and oxidative stress is imperative to allow a regulated immune response and maintain endothelial barrier integrity. Our results indicate that, considering the central role of TNF in pro-inflammatory signaling, therapeutic strategies examining pharmacological inhibition of MK2 should take potentially dangerous side effects at the level of endothelial barrier integrity into account.
Highlights
MAP kinase (MAPK)-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to stress
tumor necrosis factor (TNF) production in MK3-deficient mice is comparable to wild type, while expression in MAPK-activated protein kinase 2 (MK2)/MK3 double-knockout mice was reduced further compared to MK2-deficient mice [17]
In summary, we showed that MK2-deficient mice are highly sensitized to even very low doses of TNF, leading to hyperacute mortality
Summary
MAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. As a result of the dependency of many pro-inflammatory mRNAs on MK2-mediated stabilization, the expression of these cytokines in response to many inflammatory challenges is severely altered in MK2-deficient mice. This was first shown for TNF biosynthesis in response to a combined LPS/D-Galactosamine (D-Gal) challenge, a model of acute hepatitis [6]. Another target of p38 MAPK is MK3. TNF production in MK3-deficient mice is comparable to wild type, while expression in MK2/MK3 double-knockout mice was reduced further compared to MK2-deficient mice [17]
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