Abstract
BackgroundRecent 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.MethodsExpression 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).ResultsIn 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.ConclusionsOur 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.
Highlights
Recent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases
Results mRNA expression of proinflammatory cytokines is increased in colonic biopsies from patients with active Crohn’s disease (CD) To determine the inflammatory status of the colonic biopsies from different groups of patients, we measured mRNA expression of proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin1,beta (IL1B)
IL1B mRNA was significantly increased in sites of intestinal inflammation in patients with active CD compared to the other three groups: controls, biopsies from patients with quiescent disease and from normal mucosa of patients with active CD (Fig 1b)
Summary
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. While overexpression of microsomal prostaglandin E synthase-1 and the proinflammatory role of PGE2 have been well described in IBD [9], the role of PGD2 in IBD remains debated and there have been no reports on PGD2 in Crohn’s Disease (CD). Hokari et al suggested that LPGDS plays a proinflammatory role in the development of colitis in clinical and experimental studies [12]. They reported that the level of L-PGDS mRNA expression was increased in UC patients in parallel with disease activity. Changes in PGD2 production or in the expression of enzymes involved in its synthesis during CD are currently unknown
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