9-deoxy-delta-9-prostaglandin-d2 and Inflammatory-Bowel-Diseases

PPARgamma has been recently described as being a gene of susceptibility for Intestinal Bowel Diseases (IBD) as NOD2/CARD15 gene. IBD are pathologies due to an abnormal immune response, in genetically predisposed patients, to the bacteria of the intestinal flora. PPARgamma, known for its significant role in adipogenesis, is strongly expressed by the epithelial cells of the colon mucosa. PPARgamma 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. A deficit of PPARgamma in patients with ulcerative colitis has been highlighted, that could in part explain the acute inflammation. In addition, bacteria, including those of the commensal flora, are able to regulate PPARgamma. Toll Like Receptor-4 (TLR-4), responsible for the recognition of bacterial motif as lipopolysaccharide (LPS), is implicated in PPARgamma regulation and its anti-inflammatory properties. All these arguments make of PPARgamma a very interesting therapeutic target for the treatment of IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bacterial Physiological Phenomena; Colitis, Ulcerative; Crohn Disease; Eicosanoids; Fatty Acids, Omega-3; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intestinal Mucosa; Ligands; Lipid Metabolism; Mice; PPAR gamma; Prostaglandin D2; Thiazolidinediones; Toll-Like Receptor 4

Therapeutic interventions in the case of gastrointestinal disease are based on the understanding of the role of different inflammatory mediators. Reactive O2 and N2 metabolites are involved in IBD. Pro-inflammatory cytokines, apoptosis signalling and redox-response transcription factors are depended on free radicals. NO activates COX enzymes. PGE2 negatively modulates induction of NO synthase by interleukins and therefore regulation of gastric mucosal integrity by endogenous NO depends on arachidonic acid cascade. PG-s have pro-inflammatory and anti-inflammatory effects on the immune system. Dietary PUFA-s and eicosanoids have potential effects on the modulation of inflammatory processes and immune cells. The cholesterol level lowering activity of several cytokines and colony stimulating factor can be observed. Therapeutic efficacy of N-3 PUFA is described in cases of patients with chronic gastrointestinal disorders, but N-3 PUFA-s only delay early relapse of ulcerative colitis in remission. TNF is known as a pleiotropic cytokine. Strategies for TNF in IBD is very important part of therapeutical approaches. Therapy with infliximab and related ones are encouraging in critical cases. It is also believed recently, that NF-kappaB also may be a target of IBD treatment. It became known, that oxidized LDL can inhibit LPS-induced binding of the NF-kappaB to DNA and the subsequent expression of TNF-alpha and interleukin-1beta in macrophages as well as oxidized LDL modulates activation of NF-kappaB in mononuclear phagocytes by altering the degradation of I-kappaBs. 15-d-PGJ2 inhibits multiple steps in the NF-kappaB signaling pathway. 15-d-PGJ2 metabolite binds PPAR-gamma promotes adipocyte differentiation. PPAR-gamma ligand inhibits growth of cells through induction of apoptosis. Several nutritional polyphenols (the secondary metabolites of plants) are COX2 and/or LOX inhibitors and iNOS activators. The moderate nutritional customs with natural antioxidants can help restore to normal function of gastrointestinal tract, but the immoderate consumption of vitamins and polyphenol type antioxidant molecules is contraindicated.

Topics: Antibodies, Monoclonal; Antioxidants; Apoptosis; Cytokines; Enzyme Activation; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Flavonoids; Free Radicals; Humans; Hypolipidemic Agents; I-kappa B Proteins; Inflammatory Bowel Diseases; Infliximab; Interleukin-1; Interleukins; Lipoproteins, LDL; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nutritional Physiological Phenomena; Oxidation-Reduction; Phenols; Polyphenols; PPAR gamma; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Signal Transduction; Transcription Factors; Triglycerides; Tumor Necrosis Factor-alpha

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Crohn Disease; Humans; Inflammatory Bowel Diseases; PPAR gamma; Prostaglandin D2; Thiazolidinediones