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AICAR inhibits NF?B DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages.

ABSTRACT: 5-aminoimidazole-4-carboxamide-1-?-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-?-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - ?B (NF?B) by LPS, it prevented the recruitment of NF?B 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 HIF1?-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 NF?B and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NF?B and STAT3 to modulate inflammatory responses.

SUBMITTER: Kirchner J

PROVIDER: S-EPMC5958102 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Kirchner Johannes J Brüne Bernhard B Namgaladze Dmitry D

Scientific reports 20180517 1

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 con ...[more]

PMID: 29773845

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Dataset Information

AICAR inhibits NF?B DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages.

Publications

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

Similar Datasets

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