5-aminoimidazole-4-carboxamide ribonucleoside and AMP-activated protein kinase inhibit signalling through NF-κB.
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.
Katerelos
Marina
M
IBAS, Kronheimer Block, Austin Hospital, Heidelberg, Victoria, Australia. Marina.KATERELOS@austin.org.au
Mudge
Stuart J
SJ
Stapleton
David
D
Auwardt
Russell B
RB
Fraser
Scott A
SA
Chen
C-G
CG
Kemp
Bruce E
BE
Power
David A
DA
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D050527:Mesangial Cells / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010629:Phenformin / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D012265:Ribonucleotides; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D000620:Aminoimidazole Carboxamide; D011392:Proline; D010629:Phenformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide