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首页> 外文期刊>Clinical and Experimental Immunology: An Official Journal of the British Society for Immunology >Mechanism of glutamine inhibition of cytosolic phospholipase a(2) (cPLA(2)): Evidence of physical interaction between glutamine-Induced mitogen-activated protein kinase phosphatase-1 and cPLA(2)
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Mechanism of glutamine inhibition of cytosolic phospholipase a(2) (cPLA(2)): Evidence of physical interaction between glutamine-Induced mitogen-activated protein kinase phosphatase-1 and cPLA(2)

机译：谷氨酰胺抑制胞质磷脂酶a（2）（cPLA（2））的机制：谷氨酰胺诱导的丝裂原活化蛋白激酶磷酸酶-1和cPLA（2）之间发生物理相互作用的证据

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摘要

Non-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.
机译：非必需氨基酸L-谷氨酰胺（Gln）通过灭活胞质磷脂酶A（2）（cPLA（2））具有抗炎活性。我们以前表明，Gln通过诱导MAPK磷酸酶-1（MKP-1）使p38丝裂原活化的蛋白激酶（MAPK）（cPLA（2）磷酸化的主要激酶）去磷酸化而间接失活cPLA（2）。在这项研究中，我们调查了cPLA（2）Gln失活的确切机制。在脂多糖（LPS）处理的小鼠中，Gln注射导致磷酸化cPLA（2）（p-cPLA（2））的去磷酸化，这与MlnP-1的快速Gln诱导相吻合。 MKP-1小干扰RNA（siRNA）废除了Gln诱导MKP-1的能力以及cPLA（2）的去磷酸化作用。免疫共沉淀和原位邻近连接测定揭示了MKP-1和p-cPLA（2）之间的物理相互作用。在过敏性哮喘的小鼠模型中，我们还证明了MKP-1和p-cPLA（2）之间的物理相互作用。此外，Gln抑制了各种过敏性哮喘表型，例如嗜中性粒细胞和嗜酸性粒细胞募集进入气道，气道中T辅助2型（Th2）细胞因子[白介素（IL）-4，IL-5和IL-13]，气道高反应性，粘蛋白的生产和代谢产物（白三烯B-4和血小板活化因子）通过以MKP-1依赖性方式抑制cPLA（2）。这些数据表明，MKP-1除p38外还使用cPLA（2）作为底物，进一步增强了Gln的抗炎作用。

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