Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn’s disease, is a multifactorial inflammatory disease of the small intestine and colon. Many investigators have reported that l-glutamine (Gln) therapy improves outcomes of experimental colitis models, although the mechanism is not fully understood. Regarding the anti-inflammatory properties of Gln, we have shown that Gln can effectively deactivate cytosolic phospholipase A2 (cPLA2) by rapid induction of MAPK phosphatase (MKP)-1. In this study, we explore the possibility that Gln ameliorates dextran sulfate sodium (DSS)-induced colitis via MKP-1 induction, resulting in inhibition of cPLA2, which has been reported to play a key role in the pathogenesis of IBD. Oral Gln intake attenuated DSS-induced colitis. Gln inhibited cPLA2 phosphorylation, as well as colonic levels of TNF-α and leukotriene (LT)B4. Gln administration resulted in early and enhanced MKP-1 induction. Importantly, MKP-1 small interfering RNA (siRNA), but not control siRNA, significantly abrogated the Gln-mediated (1) induction of MKP-1; (2) attenuation of colitis (colon length, histological abnormality, and inflammation; and (3) inhibition of cPLA2 phosphorylation and colonic levels of TNF-α and LTB4. These data indicated that Gln ameliorated DSS-induced colitis via MKP-1 induction.
Background The administration of L‐glutamine (Gln) suppresses allergic airway inflammation via the rapid upregulation of MAPK phosphatase (MKP)‐1, which functions as a negative regulator of inflammation by deactivating p38 and JNK mitogen‐activated protein kinases (MAPKs). However, the role of endogenous Gln remains to be elucidated. Therefore, we investigated the mechanism by which endogenous Gln regulates MKP‐1 induction and allergic airway inflammation in an ovalbumin‐based murine asthma model. Methods We depleted endogenous Gln levels using L‐γ‐glutamyl‐p‐nitroanilide (GPNA), an inhibitor of the Gln transporter ASCT2 and glutamine synthetase small interfering siRNA. Lentivirus expressing MKP‐1 was injected to achieve overexpression of MKP‐1. Asthmatic phenotypes were assessed using our previously developed ovalbumin‐based murine model, which is suitable for examining sequential asthmatic events, including neutrophil infiltration. Gln levels were analyzed using a Gln assay kit. Results GPNA or glutamine synthetase siRNA successfully depleted endogenous Gln levels. Importantly, homeostatic MKP‐1 induction did not occur at all, which resulted in prolonged p38 MAPK and cytosolic phospholipase A2 (cPLA2) phosphorylation in Gln‐deficient mice. Gln deficiency augmented all examined asthmatic reactions, but it exhibited a strong bias toward increasing the neutrophil count, which was not observed in MKP‐1‐overexpressing lungs. This neutrophilia was inhibited by a cPLA2 inhibitor and a leukotriene B4 inhibitor but not by dexamethasone. Conclusion Gln deficiency leads to the impairment of MKP‐1 induction and activation of p38 MAPK and cPLA2, resulting in the augmentation of neutrophilic, more so than eosinophilic, airway inflammation.
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