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Title: 5-aminoimidazole-4-carboxamide ribonucleoside and AMP-activated protein kinase inhibit signalling through NF-κB.
Austin Authors: Katerelos, Marina ;Mudge, Stuart J;Stapleton, David;Auwardt, Russell B;Fraser, Scott A;Chen, C-G;Kemp, Bruce E;Power, David Anthony
Affiliation: IBAS, Kronheimer Block, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 20-Apr-2010
Publication information: Immunology and Cell Biology 2010; 88(7): 754-60
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.
Gov't Doc #: 20404837
DOI: 10.1038/icb.2010.44
Journal: Immunology and cell biology
Type: Journal Article
Subjects: AMP-Activated Protein Kinases.metabolism
Aminoimidazole Carboxamide.analogs & derivatives.pharmacology
Anti-Inflammatory Agents.pharmacology
Cells, Cultured
DNA-Binding Proteins.antagonists & inhibitors
Endothelial Cells.enzymology.metabolism
Enzyme Activation.drug effects
HeLa Cells
Mesangial Cells.enzymology.metabolism
NF-kappa B.antagonists & inhibitors.physiology
Proline.analogs & derivatives.pharmacology
Appears in Collections:Journal articles

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