Novel anti-inflammatory action of 5-aminoimidazole-4-carboxamide ribonucleoside with protective effect in dextran sulfate sodium-induced acute and chronic colitis.
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 kappaB (NF-kappaB) 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-kappaB 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.
Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada.
Aiping
A
Bai
Michael
M
Yong
Allan G
AG
Ma
Yanbing
Y
Ma
Carolyn R
CR
Weiss
Qingdong
Q
Guan
Charles N
CN
Bernstein
Zhikang
Z
Peng
D000208:Acute Disease; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015153:Blotting, Western; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D016264:Dextran Sulfate; D017868:Cyclic AMP-Dependent Protein Kinases; C031143:AICA ribonucleotide