PPAR ROLE IN IBD
The peroxisome proliferator activated receptor gamma (PPAR gamma) is a nuclear receptor highly expressed in the colon and playing a key role in bacterial-induced inflammation.
Gene of susceptibility
PPAR gamma has been described recently as being a gene of susceptibility for Intestinal Bowel Diseases (IBD), as the NOD2/CARD15 gene. IBD are pathologies due to an abnormal immune response, in genetically predisposed patients, to the bacteria of the intestinal flora. PPAR gamma, known for its significant role in adipogenesis, is strongly expressed by the epithelial cells of the colon mucosa. PPAR gamma is implicated in the regulation of inflammation. Indeed, agonists of this nuclear receptor decrease strongly the intensity of inflammation during experimental colitis induced by chemical agents.
Explaining acute inflammation
A deficit of PPAR gamma in patients with ulcerative colitis has been highlighted, which could, in part, explain the acute inflammation. In addition, bacteria, including those of the commensal flora, are able to regulate PPAR gamma. Toll-like Receptor-4 (TLR-4), responsible for the recognition of bacterial motif as lipopolysaccharide (LPS), is implicated in PPAR gamma regulation and its anti-inflammatory properties. All these arguments make of PPAR gamma a very interesting therapeutic target for the treatment of IBD (Rousseaux C, Desreumaux P.J Soc Biol. 2006; 200 (2):121-31).
Regulation of colon inflammation
Regulation of colon inflammation by this receptor has been well demonstrated in many experimental models of colitis, but also in patients with ulcerative colitis, characterized by impaired expression of PPAR gamma confined to their colon epithelial cells. Recent data showing that PPAR gamma was the major functional receptor mediating the common aminosalicylate activities in inflammatory bowel diseases (IBD), have also reinforced the roles of this receptor in the control of intestinal inflammation.
A new class of compounds emerging
Thus, the emerging therapeutic strategies targeting this receptor are leading to the development of a new class of compounds that would be indicated in IBD (Dubuquoy L et al.,Gut. 2006 Sep;55 (9):1341-9).