SummaryNon-essential amino acid L-glutamine (Gln) possesses anti-inflammatory activity via deactivating cytosolic phospholipase A 2 (cPLA 2 ). We showed previously that Gln deactivated cPLA 2 indirectly via dephosphorylating p38 mitogen-activated protein kinase (MAPK), the major kinase for cPLA 2 phosphorylation, through inducing MAPK phosphatase-1 (MKP-1). In this study, we investigated the precise mechanism underlying Gln deactivation of cPLA 2 . In lipopolysaccharide (LPS)-treated mice, Gln injection resulted in dephosphorylation of phosphorylated cPLA 2 (p-cPLA 2 ), which coincided with rapid Gln induction of MKP-1. MKP-1 small interfering RNA (siRNA) abrogated the ability of Gln to induce MKP-1 as well as the dephosphorylation of cPLA 2 . Co-immunoprecipitation and in-situ proximity ligation assay revealed a physical interaction between MKP-1 and p-cPLA 2 . In a murine model of allergic asthma, we also demonstrated the physical interaction between MKP-1 and p-cPLA 2 . Furthermore, Gln suppressed various allergic asthma phenotypes, such as neutrophil and eosinophil recruitments into the airway, airway levels of T helper type 2 (Th2) cytokines [interleukin (IL)-4, IL-5 and IL-13], airway hyperresponsiveness, mucin production and metabolites (leukotriene B 4 and platelet-activating factor) through inhibiting cPLA 2 in a MKP-1-dependent manner. These data suggest that MKP-1 uses cPLA 2 , in addition to p38, as a substrate, which further potentiates the anti-inflammatory action of Gln.
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