It has been shown that mice lacking
It has been shown that mice lacking SMAD2 in T cells do not develop spontaneous lymphoproliferative autoimmunity (Malhotra et al., 2010). Further, FOXO1 is known to activate proinflammatory MCP-1 and IL-6 (Ito et al., 2009). To this end, we also validated the downstream target FOXO1 and SMAD2 after FAAH inhibition. Interestingly, FAAH inhibition increased FOXO1 and decreased SMAD2, suggesting a mechanism that suppresses the inflammatory response in acute colitis. Taken together, changes in the expression of these miRNAs in response to FAAH-II treatment are considered to be a potential molecular mechanism, which can lead to the decreased cytokine and SMAD2 expression and increased FOXO1 expression observed in this study.
Acknowledgments This study was supported in part by grants from R56DK087836 (UPS) and P01AT003961 (MN and PN) and the Intramural Research Program, NIA (DT), NIH. We thank Prof. Edsel Pena, director of the Biometry Core of the Center for Colon Cancer Research (CCCR) for his advice on statistical analysis.
The endocannabinoid system includes two G-protein-coupled receptors (CB and CB), endogenous ligands, named endocannabinoids (ECs), that bind to these receptors and several enzymes responsible for the biosynthesis and the degradation of these ECs (ex: fatty Fmoc-His(Boc)-OH.CHA amide hydrolase (FAAH), monoacylglycerol lipase (MAGL))., , It has been established that the modulation of the endocannabinoid system through the activation of cannabinoid receptors and the inhibition of ECs degradation enzymes consists in a promising therapeutic strategy. Indeed, this system has shown beneficial effects in several diseases like osteoporosis, pain or chronic inflammation disorders. The CB receptor is mainly expressed in the central nervous system, where it is one of the most abundant receptors. Its central location is correlated with the behavioral effects of cannabinoids: memory, cognition and motor functions. On the other hand, the CB receptor is mainly located in cells of the immune system, and involved in the immunomodulatory effects induced by cannabinoids. Because activation of CB receptors is responsible for most of the neurobehavioral effects of Δ-tetrahydrocannabinol (THC) (hypermotility, analgesia, hypothermia, catalepsy), the development of selective CB agonists without psychoactivity due to CB appears to be crucial. Current research on selective CB agonists have shown a broad spectrum of pharmacological effects, such as anti-inflammatory (JWH-133, GW-842,166X), analgesic (AM1241) and anticancer (JWH-133) activities (). FAAH is a specific enzyme of long chain fatty acids derivatives located in both central and peripheral levels. It degrades ECs as anandamide (AEA), palmitoylethanolamide (PEA) or oleoylethanolamide (OEA). Recently, FAAH inhibitors were developed to block the rapid catabolism of AEA and prolong its action. Among these FAAH inhibitors, URB597 is one of the most potent known to date () and is particularly active on acute, inflammatory or neuropathic pain,, , and protects against experimental colitis. Our group research aims to develop new treatments for inflammatory bowel diseases (IBD), which two main forms are Crohn’s disease and ulcerative colitis. These diseases affect more than 2.2million people in Europe and are characterized by an inflammation of the gastrointestinal tract due to a hyperactivity of the immune system. The endocannabinoid system is implicated in gut homeostasis, gastrointestinal motility and IBD., Recently, it has been demonstrated that cannabinoid receptors are overexpressed in vivo and in patients suffering from IBD., The beneficial role of CB in intestinal inflammation has been highlighted in several in vivo and in vitro studies., , , Moreover, Massa et al. showed that the genetic invalidation of FAAH in animals with 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis significantly reduced tissue inflammation. Storr et al. showed that URB597 increased survival and decreased inflammation in mice suffering from trinitrobenzene sulfonic acid (TNBS)-induced colitis.,