Regulation of sepsis-induced endothelial cell dysfunction by 5’ AMP-activated protein kinase (AMPK)
Acronym: Seda
Principal Investigator: Silke Lindenmüller
Scientific Advisor: Prof. Dr. Regine Heller
Research Area: D Sepsis related Organ Failure
Project Number: D1.12
Duration: 01.10.2011 - 30.09.2014
Module: PhD Fellowship
The Problem
The energy-sensing enzyme AMP-activated kinase (AMPK) is involved in the regulation of energy supply and stress protection in endothelial cells. The present project is aimed at investigating whether AMPK is modulated by inᴀammatory stimuli known to mediate sepsis and whether this enzymes is able to limit inflammatory responses of the endothelium and the development of endothelial dysfunction under septic conditions.
Results so far
In the first part of this project, the influence of inflammatory stimuli on AMPK activity was investigated (lipopolysaccharide (LPS), interleukin 1β (IL1β), interleukin 6 (IL6), interferon γ (IFNγ), tumor necrosis factor α (TNFα), alone or in combination). None of the tested stimuli led to an activation of AMPK as monitored by phosphorylation of the threonine 172 residue and by activity assays. In contrast, a phosphorylation at serine residue 485 was detected, but its function still needs to be studied. Interestingly, downregulation of the catalytic subunit AMPKα1 and/or α2 led to a decreased cytokine-induced expression of the adhesion molecules ICAM-1 and VCAM-1 indicating a decreased endothelial adhesivity. Our preliminary data suggest, that inhibition of AMPK by cytokines may help to limit the inflammatory response. This is in contrast to our initial hypothesis and needs further investigation with respect to the time-dependence of the effect and underlying mechanisms.
Contact
Tel.: +49 (0)3641 - 9 39 56 05
Tel.: +49 (0)3641 - 9 39 56 33
Universitätsklinikum Jena
Institut für Molekulare Zellbiologie, CMB
Hans-Knöll-Str. 2
07745 Jena