Abstract 5516: α1-AMP-activated Protein Kinase Is An Inflammatory Modulator
The adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular energy homeostasis. Recent studies with pharmacological activation of AMPK have suggested a possible role of AMPK activation in suppressing inflammatory reactions. However, many effects of AMPK activators are not AMPK dependent. Therefore, it remains unclear whether AMPK plays a physiological role in regulation of inflammation. Here we show that α1-AMPK plays a non-redundant role in the attenuation of inflammation and tissue injury in vivo. Mice deficient in α1-AMPK had increased myeloid cells in circulation. When challenged with endotoxin, the mice reacted with low counts of circulating leukocytes, increased leukocyte infiltration in major organs, high levels of blood pro-inflammatory cytokines and significant tissue damage. Macrophages, but not neutrophils and monocytes expressed α1-AMPK catalytic subunit. α1-AMPK in macrophages and endothelial cells was rapidly activated in response to inflammatory stimulus. In macrophages lacking α1-AMPK, a sustained phosphorylation of mitogen-activated protein kinase (MAPK) p38 and an increased NF-κB activation were observed. This may be the underlying mechanism for a higher inflammatory response in α1-AMPK deficient endothelial cells and macrophages compared to wild type cells following inflammatory stimuli. Our study indicates that α1-AMPK is a critical part of the physiological negative feedback for inhibition of inflammation.