Stimulators of AMP‐activated protein kinase inhibit the respiratory burst in human neutrophils

Abstract

In the present study, we have examined the potential ability of 5 0 -AMP-activated protein kinase (AMPK) to modulate NADPH oxidase activity in human neutrophils. AMPK activated with either 5 0 -aminoimidazole-4-carboxamide ribonucleoside (AICAR) or with 5 0 -AMP significantly attenuated both phorbol 12-myristate 13-acetate (PMA) and formyl methionyl leucyl phenylalanine-stimulated superoxide anion ðO À 2 Þ release by human neutrophils, consistently with a reduced translocation to the cell membrane and phosphorylation of a cytosolic component of NADPH oxidase, namely p47 phox . AMPK was found to be present in human neutrophils and to become phosphorylated in response to either AICAR or other stimulators of its enzyme activity. Furthermore, AICAR also strongly reduced PMA-dependent H 2 O 2 release, and induced the phosphorylation of c-jun N-terminal kinase 1 (p46), p38 mitogenactivated protein kinase and extracellular signal-regulated kinase. Present data demonstrate for the first time that the activation of AMPK, in states of low cellular energy charge (such as under high levels of 5 0 -AMP) or other signals, could be a factor contributing to reduce the host defense mechanisms.

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

“…This is supported by data showing that the activation of adenosine monophosphate kinases in a state of low cellular energy contributes to a reduction in host defense mechanisms. 30 The clinical importance of these neutrophil abnormalities, which are identified by a high resting oxidative burst greater than or equal to 55% and a reduced phagocytic capacity (relative GMFI Ͻ 42%), are highlighted by the observation of increased risk of infection and the association with organ failure and mortality in these patients. It is notable that this group of patients in our study had infections with multiple organisms despite antibiotic therapy within a relatively short time frame.…”

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

“…Our data suggest the following: 1) that an increase in endogenous FFA availability augments ROS generation, and 2) that AMPK activation during lipolysis probably limits this oxidative stress. Studies in which AMPK activity in the adipocyte is down-regulated by genetic means are needed to confirm this conclusion; however, it is noteworthy that a similar effect of AMPK activation on ROS generation has been observed in human endothelial cells incubated with linoleate or palmitate (10,46) and in neutrophils treated with phorbol myristate acetate (12). In both situations, AMPK activation was shown to diminish NAD(P)H oxidase activity.…”

ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK

“…In clinical studies, ETC-1002 has not only demonstrated improved lipid profi les but also revealed signifi cantly attenuated levels of hsCRP ( 19 ), an independent risk factor for CAD and a well-established clinical biomarker of infl ammation ( 20,21 ). Pharmacological activation of AMPK has been previously shown to limit infl ammatory response in vitro and in vivo (22)(23)(24)(25)(26), and several signaling pathways, including Akt, GSK, SIRT, and NFkB, have been associated with anti-infl ammatory consequences of AMPK activation ( 17,(27)(28)(29). While the exact mechanism of AMPK-dependent regulation of the immune response remains unclear, inhibition of mitogen-activated protein kinases (MAPK), such as JNK and p38, has been recently linked to AMPK-dependent anti-infl ammatory signaling ( 30 ).…”