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.
Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain.
Juan
J
Suárez
Yanina
Y
Romero-Zerbo
Lucia
L
Márquez
Patricia
P
Rivera
Mar
M
Iglesias
Francisco J
FJ
Bermúdez-Silva
Montserrat
M
Andreu
Fernando
F
Rodríguez de Fonseca
D000293:Adolescent; D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D019804:Mesalamine / Q000627:therapeutic use*; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000893:Anti-Inflammatory Agents; D004983:Ethanolamines; D005938:Glucocorticoids; D019804:Mesalamine; D052247:Nitric Oxide Synthase Type II; D047493:PPAR alpha; D047495:PPAR gamma; D010739:Phospholipase D; D000099252:Fatty Acid Amide Hydrolases; C022203:N-acylethanolamines; C523108:NAAA protein, human