ABSTRACT
PGs play key regulatory roles in inflammation and immunity. PGD2, released from mast cells and Th2 cells during allergic responses, has recently been shown to target a novel receptor, chemoattractant receptor-homologous molecule expressed TH2 cells (CRTH2), in addition to the classic PGD (DP) receptor. CRTH2 is expressed on Th2 cells and eosinophils and mediates chemotaxis of these cells to PGD2. Thus, CRTH2 is thought to be a key receptor mediating eosinophil and Th2 cell recruitment during allergic responses. To examine the role of CRTH2 in this context in vivo, we generated CRTH2 knockout mice. Surprisingly, in an allergic inflammatory model of asthma, CRTH2 knockout mice showed enhanced eosinophil recruitment into the lung compared with wild-type littermate mice. This is consistent with our observation that CRTH2 knockout cells produce significantly higher amounts of IL-5 and IL-3 in vitro. These results suggest a nonredundant role of CRTH2 in restricting eosinophilia and allergic response in vivo.
Subject(s)
Chemotaxis, Leukocyte/immunology , Eosinophils/immunology , Interleukin-5/biosynthesis , Receptors, Immunologic/physiology , Receptors, Prostaglandin/physiology , Th2 Cells/immunology , Th2 Cells/metabolism , Animals , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cells, Cultured , Chemotaxis, Leukocyte/genetics , Down-Regulation/genetics , Down-Regulation/immunology , Eosinophilia/genetics , Eosinophilia/immunology , Eosinophils/cytology , Female , Interleukin-5/antagonists & inhibitors , Lymphocyte Activation/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Prostaglandin D2/metabolism , Prostaglandin D2/physiology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/biosynthesis , Receptors, Immunologic/deficiency , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/biosynthesis , Receptors, Prostaglandin/deficiency , Up-Regulation/genetics , Up-Regulation/immunologyABSTRACT
In human, digestive disorders are often associated with visceral pain. In these pathologies, visceral pain threshold is decreased indicating a visceral hypersensitivity. Pregabalin [CI-1008; S-(+)-3-isobutylgaba] presents antihyperalgesic actions in inflammatory somatic pain models. This study was designed to evaluate 1) the effect of injection of TNBS into the colon on visceral pain threshold, and 2) the antihyperalgesic effect of pregabalin on TNBS-induced chronic colonic allodynia. A significant decrease in the colonic pain threshold was observed in trinitrobenzene sulfonic acid (TNBS)-treated animals (17.8 +/- 1.27 versus 43.4 +/- 1.98 mm Hg). Pregabalin (30-200 mg/kg s.c.) and morphine (0.1-1 mg/kg s.c.) showed a dose-related inhibition of TNBS-induced colonic allodynia. Pregabalin did not inhibit the colonic inflammatory effect of TNBS. In normal conditions (control animals), morphine (0.3 mg/kg s.c.) significantly increased the colonic pain threshold, whereas pregabalin (200 mg/kg s.c.) did not modify the colonic pain threshold. Pregabalin suppressed the TNBS-induced colonic allodynia but did not modify the colonic threshold in normal conditions. The ability of pregabalin to block the chronic colonic allodynia indicates that it is effective in abnormal colonic hypersensitivity, suggesting a possible effect in chronic pain in irritable bowel syndrome.
