Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma.
5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.
Rousseaux
Christel
C
Institut National de la Santé et de la Recherche Medicale 0114, Physiopathologie des Maladies Inflammatoires Intestinales, CHU 59037 Lille, France.
Lefebvre
Bruno
B
Dubuquoy
Laurent
L
Lefebvre
Philippe
P
Romano
Olivier
O
Auwerx
Johan
J
Metzger
Daniel
D
Wahli
Walter
W
Desvergne
Béatrice
B
Naccari
Gian Carlo
GC
Chavatte
Philippe
P
Farce
Amaury
A
Bulois
Philippe
P
Cortot
Antoine
A
Colombel
Jean Frédéric
JF
Desreumaux
Pierre
P
D041721:3T3-L1 Cells; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008297:Male; D019804:Mesalamine / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D047495:PPAR gamma / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D019804:Mesalamine