5‐aminoimidazole‐4‐carboxamide ribonucleoside and AMP‐activated protein kinase inhibit signalling through NF‐κB

Abstract

Activation of nuclear factor‐kappa B (NF‐κB) is one of the most important pro‐inflammatory mechanisms in disease. In this study, we show that 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR), an intermediate in nucleoside metabolism, inhibits signalling by NF‐κB in three cell types, including bovine aortic endothelial cells (BAEC). The block in the NF‐κB signalling pathway occurred beyond degradation of IκB‐α and movement of p65 into the nucleus of BAEC. There was, however, reduced binding of NF‐κB from AICAR‐treated cells to a κB‐consensus oligonucleotide, suggesting that part of the mechanism was a reduction in NF‐κB DNA‐binding activity. Although AICAR is metabolized to ZMP and then adenosine, adenosine had no effect on activation of an NF‐κB reporter. ZMP, however, activates the metabolic stress‐sensing AMP‐activated protein kinase (AMPK). Transfection of active AMPK into BAEC reduced NF‐κB reporter activity compared with a kinase‐dead mutant, suggesting that part of the ability of AICAR to inhibit NF‐κB signalling is due to activation of AMPK. Inhibition of NF‐κB signalling may be important in the anti‐inflammatory action of drugs such as sulfasalazine and methotrexate, which led to the accumulation of AICAR within target cells.

Genetic Deletion of Catalytic Subunits of AMP-activated Protein Kinase Increases Osteoclasts and Reduces Bone Mass in Young Adult Mice

“…Endothelial cells also express both ␣ subunits of AMPK, and conflicting reports of their roles have also emerged (40). Consistent with our observations in osteoclast progenitor cells, overexpression of AMPK␣1 or AMPK activation by AICAR also reduces NFB signaling in aortic endothelial cells (41). A similar study in endothelial cells demonstrated that AMPK attenuates NFB activation via direct phosphorylation of IKK␤ on Ser-177 and Ser-181 by AMPK␣2 but not AMPK␣1 (40).…”

Decreased Expression of Nicotinamide Phosphoribosyltransferase in Patients with Juvenile Idiopathic Arthritis Receiving Methotrexate

“…MTX is known to inhibit aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, which results in accumulation of AICAR that further sensitizes AMP-activated protein kinase (AMPK) 11 . AMPK has been shown to induce NAMPT transcription in glucose-restricted skeletal myoblasts, which may appear to contradict our findings here; however, AICAR (through activation of AMPK) has also been shown to inhibit nuclear factor-κB (NF-κB) 12,13 . NF-κB has been shown to induce NAMPT activity, thus inhibition of this important proinflammatory transcription factor in MTX-treated patients may contribute to lower NAMPT concentrations in these patients.…”

Activation of AMPK improves inflammation and insulin resistance in adipose tissue and skeletal muscle from pregnant women

“…Furthermore, the pathway(s) involved in AMPK-induced suppression of inflammation and insulin sensitivity remains yet to be elucidated. Recent studies show AICAR and phenformin inhibits LPS-induced NF-κB signalling and also the transcription of NF-κB-dependent genes [15]. NF-κB is a transcription factor that regulates the expression of pro-inflammatory mediators and has been described to play an important role in the pathogenesis of diabetes and its associated complications [23].…”