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AICAR inhibits inflammation in MRL/lpr mouse mesangial cells
Author(s) -
Radjavi Ali,
Edelestein Rachel,
Peairs Abby,
Giri Shailendra,
Reilly Christopher M
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.942.12
Subject(s) - ampk , pi3k/akt/mtor pathway , protein kinase b , tensin , chemistry , pten , inflammation , protein kinase a , endocrinology , medicine , kinase , signal transduction , cancer research , biology , biochemistry
MRL/MPJ‐Faslpr (MRL/lpr) mice develop lupus‐like disease similar to human systemic lupus erythematosus, including immune complex deposition in the kidney which triggers the release of proteolytic enzymes, inflammatory mediators, cytokines, reactive oxygen species, and nitric oxide. Recent reports show that 5‐amino‐4‐imidazole carboxamide riboside (AICAR), a pharmacological activator of AMP‐activated protein kinase (AMPK), inhibits the LPS‐induced production of pro‐inflammatory cytokines. In our current studies, we sought to determine the mechanism by which AMPK decreases inflammation. Cultured mesangial cells from MRL/lpr mice were treated with AICAR and stimulated with LPS/IFN‐γ. AICAR dose dependently decreased iNOS, TNF‐α, and IL‐6 production in LPS/IFN‐γ stimulated mesangial cells. In pursuit of a mechanism we showed that AMPK activation induces phosphatase and tensin homolog (PTEN) expression which inhibits LPS‐induced PI3K/Akt/mTOR signaling inflammatory cascade. An adenosine kinase inhibitor blocked the ability of AICAR to activate AMPK and its downstream target PTEN, preventing inhibition of Akt. Interestingly, the p38 and IκB/NF‐κB signaling pathways were unaffected by AICAR treatment. Taken together, these observations suggest that AICAR specifically targets Akt signaling via PTEN activation and that AMPK may serve as a therapeutic target in inflammatory disease.