Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids

Studies in animal models and humans suggest anti-inflammatory roles on the N acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.

Journal Article; Research Support, Non-U.S. Gov't;

This study was supported by grants to FRdF from the European Union’s 7th Framework Programme (Health-F2-2008-223713, REPROBESITY); the following grants from the Spanish Ministry of Science and Innovation (SAF2010-20521); National Institute of Health ‘‘Carlos III’’ (PI07/1226, PI07/0880 and PI 07/0953), Red de Trastornos Adictivos-UE-ERDF (RD06/0001/0000) and El Centro de Investigación Biomédica en Red de Fisiopatología de Obesidad y Nutrición; grants from the Consejería de Economía, Innovación y Ciencia de la Junta de Andalucía, UE/ERDF (CTS-433 and PI45403); and a grant from the Consejería de Salud de la Junta de Andalucía (PI0232/2008), Spain. FJBS holds a Miguel Servet research contracts CD07/00283, and JS holds a Sara Borrell postdoctoral contract CD08/00203, both from the National Institute of Health ‘‘Carlos III’’, Madrid, Spain.