AICAR inhibits NFκB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages

Scientific Reports
Johannes KirchnerDmitry Namgaladze

Abstract

5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electro...Continue Reading

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Citations

Jun 13, 2019·Science Signaling·Dubek KazykenDiane C Fingar
Jul 5, 2019·International Journal of Molecular Sciences·Lisa Maria MartinEllen Niederberger
Feb 23, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sneha SinghAshok Kumar
Oct 12, 2018·International Journal of Molecular Sciences·Claire L Lyons, Helen M Roche
Jun 21, 2020·Investigative Ophthalmology & Visual Science·Selikem Abla Nuwormegbe, Sun Woong Kim
Oct 27, 2020·American Journal of Physiology. Renal Physiology·Xiaogao JinYanlin Wang
Jan 30, 2021·Frontiers in Cell and Developmental Biology·Qiuhua YangYuqing Huo
Feb 11, 2021·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Samuel LundtShinghua Ding
Sep 18, 2020·Molecular Genetics and Metabolism Reports·Randall C MazzarinoGuido N Vacano

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Methods Mentioned

BETA
nuclear translocation
immunoprecipitation
ChIP
electrophoretic mobility shift
flow cytometry
PCR

Software Mentioned

GraphPad
Prism

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