Prostaglandin E2, Produced by Mast Cells in Colon Tissues from Patients with Irritable Bowel Syndrome, Contributes to Visceral Hypersensitivity in Mice

Abstract Background & Aims Visceral hypersensitivity is common in patients with irritable bowel syndrome (IBS). We investigated whether inflammatory molecules, such as histamine and proteases, activate prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2) to increase the synthesis of prostaglandin E2 (PGE2) by mast cells, which activates the receptor PTGER2 (also called EP2) in the dorsal root ganglia to promote visceral hypersensitivity. Methods We used an ELISA to measure levels of spontaneous release of molecules from mast cells in colonic mucosa from patients with IBS with diarrhea (IBS-D; 18 women and 5 men; ages 28 to 60 y), healthy individuals (controls, n=24), mice, and rats. We measured visceromotor responses to colorectal distension in rodents following intracolonic administration of colon biopsy supernatants, histamine, PGE2, a small interfering RNA against EP2, or an agonist of F2R like trypsin receptor 1 (F2RL1, also called PAR2). We investigated the role of COX2, produced by mast cells, in mediation of visceral hypersensitivity using mice with the Y385F substitution in Ptgs2 (Ptgs2Y385F mice), mast cell-deficient (W/WV) mice, and W/WV mice given injections of mast cells derived from wild-type or Ptgs2Y385F mice. Results Colon biopsies from patients with IBS-D had increased levels of PGE2, based on ELISA, and COX2 mRNA and protein, compared with control biopsies. Immunohistochemistry showed that most of the COX2 was in mast cells. Intracolonic infusions of rats with IBS-D biopsy supernatants generated a 3–4-fold increase in visceromotor responses to colorectal distension; this was associated with significant increases in PGE2, histamine, and tryptase in the colonic mucosa. These increases were prevented by a mast cell stabilizer, COX2 inhibitor, or knockdown of EP2. Intracolonic administration of supernatants from biopsies of patients with IBS-D failed to induce visceral hypersensitivity or increase the level of PGE2 in W/WV and Ptgs2Y385F mice. Reconstitution of mast cells in W/WV mice restored the VH response. Conclusions Abnormal synthesis of PGE2 by colonic mast cells appears to induce visceral hypersensitivity in patients with IBS-D.