prostaglandin-d2 and Crohn-Disease

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

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

In healthy gut enteric glial cells (EGC) are essential to intestinal epithelial barrier (IEB) functions. In Crohn's Disease (CD), both EGC phenotype and IEB functions are altered, but putative involvement of EGC in CD pathogenesis remains unknown and study of human EGC are lacking. EGC isolated from CD and control patients showed similar expression of glial markers and EGC-derived soluble factors (IL6, TGF-β, proEGF, GSH) but CD EGC failed to increase IEB resistance and healing. Lipid profiling showed that CD EGC produced decreased amounts of 15-HETE, 18-HEPE, 15dPGJ2 and 11βPGF2α as compared to healthy EGC. They also had reduced expression of the L-PGDS and AKR1C3 enzymes. Produced by healthy EGC, the 11βPGF2 activated PPARγ receptor of intestinal epithelial cells to induce cell spreading and IEB wound repair. In addition to this novel healing mechanism our data show that CD EGC presented impaired ability to promote IEB functions through defect in L-PGDS-AKR1C3-11βPGF2α dependent pathway.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aldo-Keto Reductase Family 1 Member C3; Caco-2 Cells; Cells, Cultured; Coculture Techniques; Crohn Disease; Dinoprost; Eicosapentaenoic Acid; Epithelial Cells; Female; Humans; Hydroxyeicosatetraenoic Acids; Intestinal Mucosa; Intestines; Male; Middle Aged; Prostaglandin D2; Wound Healing; Young Adult

Recent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases. We investigated the expression of PGD2 metabolic pathway actors in Crohn's disease (CD) and the ability of the enteric nervous system (ENS) to produce PGD2 in inflammatory conditions.. Expression of key actors involved in the PGD2 metabolic pathway and its receptors was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in colonic mucosal biopsies of patients from three groups: controls, quiescent and active CD patients. To determine the ability of the ENS to secrete PGD2 in proinflammatory conditions, Lipocalin-type prostaglandin D synthase (L-PGDS) expression by neurons and glial cells was analyzed by immunostaining. PGD2 levels were determined in a medium of primary culture of ENS and neuro-glial coculture model treated by lipopolysaccharide (LPS).. In patients with active CD, inflamed colonic mucosa showed significantly higher COX2 and L-PGDS mRNA expression, and significantly higher PGD2 levels than healthy colonic mucosa. On the contrary, peroxysome proliferator-activated receptor Gamma (PPARG) expression was reduced in inflamed colonic mucosa of CD patients with active disease. Immunostaining showed that L-PGDS was expressed in the neurons of human myenteric and submucosal plexi. A rat ENS primary culture model confirmed this expression. PGD2 levels were significantly increased on primary culture of ENS treated with LPS. This production was abolished by AT-56, a specific competitive L-PGDS inhibitor. The neuro-glial coculture model revealed that each component of the ENS, ECG and neurons, could contribute to PGD2 production.. Our results highlight the activation of the PGD2 metabolic pathway in Crohn's disease. This study supports the hypothesis that in Crohn's disease, enteric neurons and glial cells form a functional unit reacting to inflammation by producing PGD2.

Topics: Adolescent; Adult; Aged; Animals; Cells, Cultured; Coculture Techniques; Crohn Disease; Cyclooxygenase 2; Cytokines; Enteric Nervous System; Female; Humans; Intestinal Mucosa; Intramolecular Oxidoreductases; Lipocalins; Male; Middle Aged; Myenteric Plexus; Neuroglia; Neurons; PPAR gamma; Prostaglandin D2; Rats; RNA, Messenger; Severity of Illness Index; Submucous Plexus; Young Adult

Topics: Catalase; Colon; Colonic Neoplasms; Crohn Disease; Dinoprostone; Humans; Immunoenzyme Techniques; Intestinal Mucosa; Luminescent Measurements; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Reference Values