Abstract
AMP-activated protein kinase (AMPK) is an important cellular energy sensor that is responsible for maintaining systemic and cellular energy balance. Its role in intestinal inflammation remains unclear. Recent studies indicate that AMPK activation initiated by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) participates in modulating inflammatory responses. Inflammatory bowel disease (IBD) has been characterized by sustained intestinal mucosa inflammation, caused mainly by excessive macrophage activation and T helper type 1 (Th1) and Th17 immune responses. Thus, we sought to determine the effect of AICAR on inflammatory responses of murine models of IBD. Mice with acute or chronic colitis induced by dextran sulfate sodium (DSS) were treated with or without AICAR. Body weight and colon inflammation were evaluated, and production of proinflammatory cytokines in colon tissues was determined. Nuclear factor κB (NF-κB) activation in colon tissues was assayed, and Th1 and Th17 cell responses were also evaluated. By inducing AMPK activation, AICAR had a therapeutic effect in ameliorating acute and chronic DSS-induced murine colitis as shown by reduced body weight, loss and significant attenuation in clinical symptoms, and histological inflammation. Moreover, AICAR treatment inhibited NF-κB activation in macrophages, reduced levels of Th1- and Th17-type cytokines in colon tissues, and down-regulated Th1 and Th17 cell responses during the progress of acute and chronic experimental colitis. AICAR acts as a central inhibitor in immune responses of experimental colitis. Our data show that AICAR-initiated AMPK activation may represent a promising alternative to our current approaches to suppress intestinal inflammation in IBD.
Footnotes
This work was supported in part by the Canadian Institutes of Health Research [Grant ROP-92387]; the National Natural Scientific Foundation of China [Grant 30860108]; and UCB Canada and conducted using facilities of the Manitoba Institute of Child Health, Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.164954.
-
ABBREVIATIONS:
- IBD
- inflammatory bowel disease
- TNF
- tumor necrosis factor
- IL
- interleukin
- Th
- T helper cell
- IFN
- interferon
- AICAR
- 5-aminoimidazole-4-carboxamide ribonucleoside
- AMPK
- AMP-activated protein kinase
- NF-κB
- nuclear factor κB
- LPS
- lipopolysaccharide
- DSS
- dextran sulfate sodium
- MLN
- mesenteric lymph node (cell)
- LPMC
- lamina propria mononuclear cell
- HBSS
- Hanks' balanced salt solution
- mAb
- monoclonal antibody
- ELISA
- enzyme-linked immunosorbent assay(s)
- iNOS
- inducible nitric oxide synthase
- PCR
- polymerase chain reaction
- RORγt
- all-trans retinoic acid orphan receptor γ
- T-bet
- T-box expressed in T cells
- p-AMPK
- phosphorylated-AMPK.
- Received December 17, 2009.
- Accepted February 23, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|