title: Glutamine suppresses airway neutrophilia by blocking cytosolic phospholipase A(2) via an induction of MAPK phosphatase-1.
abstract: Neutrophils are inflammatory cells that may contribute in a crucial way to the pathophysiology of steroid-resistant severe asthma. We previously reported that the nonessential amino acid l-glutamine (Gln) suppressed the recruitment of neutrophils into the airway in a murine model of asthma. In this study, we investigated the mechanisms by which Gln exerts beneficial effects in airway neutrophilia. We used the model we previously developed, which is suitable for examining sequential early asthmatic events, including neutrophil infiltration. Gln suppressed airway neutrophilia in a CXC chemokine-independent way. Airway neutrophilia was associated with cytosolic phospholipase A(2) (cPLA(2)) and 5-lipoxygenase (5-LO) activities. p38 MAPK, the upstream pathway of cPLA(2) and 5-LO, played a key role in inducing airway neutrophilia. Gln inhibited not only the phosphorylation of cPLA(2) and p38 MAPK but also leukotriene B(4) levels in the airways. Gln induced the early induction of MAPK phosphatase-1 (MKP-1) protein, a negative regulator of p38. MKP-1 small interfering RNA abrogated all the effects of Gln. Our results suggest that pathways involving p38/cPLA(2)/5-LO have a major role in airway neutrophilia. Gln suppresses airway neutrophilia via inhibiting p38 MAPK and its downstream pathways in an MKP-1-dependent way, which may provide a novel therapeutic strategy for pulmonary neutrophilic inflammatory diseases.
authors.affiliation: Department of Immunology, Chonbuk National University Medical School, Jeonju, Chonbuk 561-182, Republic of Korea.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Lee
authors.forename: Hae-Kyoung
authors.initials: HK
authors.lastname: Kim
authors.forename: June-Mo
authors.initials: JM
authors.lastname: Kim
authors.forename: Otgonzaya
authors.initials: O
authors.lastname: Ayush
authors.forename: Suhn-Young
authors.initials: SY
authors.lastname: Im
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Oh
authors.forename: Hern-Ku
authors.initials: HK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000276:immunology; D003600:Cytosol / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005973:Glutamine / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D012137:Respiratory System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D064801:Phospholipase A2 Inhibitors; D005973:Glutamine; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D048051:p38 Mitogen-Activated Protein Kinases; D054467:Phospholipases A2; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse