title: Mechanism of glutamine inhibition of cytosolic phospholipase a2 (cPLA2 ): Evidence of physical interaction between glutamine-Induced mitogen-activated protein kinase phosphatase-1 and cPLA2.
abstract: Non-essential amino acid L-glutamine (Gln) possesses anti-inflammatory activity via deactivating cytosolic phospholipase A2 (cPLA2 ). We showed previously that Gln deactivated cPLA2 indirectly via dephosphorylating p38 mitogen-activated protein kinase (MAPK), the major kinase for cPLA2 phosphorylation, through inducing MAPK phosphatase-1 (MKP-1). In this study, we investigated the precise mechanism underlying Gln deactivation of cPLA2 . In lipopolysaccharide (LPS)-treated mice, Gln injection resulted in dephosphorylation of phosphorylated cPLA2 (p-cPLA2 ), 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 cPLA2 . Co-immunoprecipitation and in-situ proximity ligation assay revealed a physical interaction between MKP-1 and p-cPLA2 . In a murine model of allergic asthma, we also demonstrated the physical interaction between MKP-1 and p-cPLA2 . 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 B4 and platelet-activating factor) through inhibiting cPLA2 in a MKP-1-dependent manner. These data suggest that MKP-1 uses cPLA2 , in addition to p38, as a substrate, which further potentiates the anti-inflammatory action of Gln.
authors.affiliation: Department of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: H-K
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Department of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Y-D
authors.initials: YD
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Histology and Embryology, Yanbian University Medical College, YanJi City, China.
authors.forename: Z Wu
authors.initials: ZW
authors.lastname: Jin
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Im
authors.affiliation: Department of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: H-K
authors.initials: HK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005973:Glutamine / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding
chemical_list: D005973:Glutamine; D054510:Phospholipases A2, Cytosolic; D054638:Dual Specificity Phosphatase 1
keywords: MKP-1; asthma; cPLA2; glutamine; inflammation