首页> 美国卫生研究院文献>Infection and Immunity >Role of Protein Tyrosine Kinase p53/56lyn in Diminished Lipopolysaccharide Priming of Formylmethionylleucyl- phenylalanine-Induced Superoxide Production in Human Newborn Neutrophils
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Role of Protein Tyrosine Kinase p53/56lyn in Diminished Lipopolysaccharide Priming of Formylmethionylleucyl- phenylalanine-Induced Superoxide Production in Human Newborn Neutrophils

机译:酪氨酸蛋白激酶p53 / 56lyn在人新生儿嗜中性粒细胞中甲酰甲硫酰基亮氨酰-苯丙氨酸诱导的超氧化物生成的脂多糖减少中的作用

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摘要

Human newborns are more susceptible than adults to bacterial infection. With gram-negative bacteria, this may be due to a diminished response of newborn leukocytes to lipopolysaccharide (LPS). Since protein tyrosine kinase inhibition abolishes LPS priming in adult cells, we hypothesized that protein tyrosine kinases may have a critical role in LPS priming of polymorphonuclear neutrophils (PMNs) and that newborn PMNs may have altered protein tyrosine kinase activities. In the present study, we investigated the role of src family protein tyrosine kinases in the LPS response of newborn PMNs compared to adult cells. In a respiratory assay, the LPS-primed increase in formylmethionylleucylphenylalanine (fMLP)-triggered O2 release by adult PMNs was greatly decreased by PP1 [4-amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine], a src kinase inhibitor, to the level of untreated newborn PMNs, in which LPS failed to prime. LPS activated the src-like kinases p59hck (HCK) and p58fgr (FGR) in both adult and newborn PMNs but increased the activation of p53/56lyn (LYN) only in adult cells. In newborn PMNs, LYN was highly phosphorylated independent of LPS. We evaluated subcellular fractions of PMNs and found that the phosphorylated form of LYN was mainly in the Triton-extractable, cytosolic fraction in adult PMNs, while in newborn cells it was located mainly in Triton-insoluble, granule- and membrane-associated fractions. In contrast, the phosphorylated mitogen-activated protein kinases ERK1/2 and p38 were mainly detected in the cytosol in both adult and newborn PMNs. These data indicate a role for LYN in the regulation of LPS priming. The trapping of phosphorylated LYN in the membrane-granule fraction in newborn PMNs may contribute to the deficiency of newborn cells in responding to LPS stimulation.
机译:人类新生儿比成年人更容易受到细菌感染。对于革兰氏阴性细菌,这可能是由于新生白细胞对脂多糖(LPS)的反应减弱所致。由于蛋白酪氨酸激酶抑制作用消除了成年细胞中LPS引发,因此我们假设蛋白酪氨酸激酶可能在多形核中性粒细胞(PMN)的LPS引发中起关键作用,而新生PMN可能改变了蛋白酪氨酸激酶活性。在本研究中,我们调查了与成人细胞相比,src家族蛋白酪氨酸激酶在新生PMNs的LPS反应中的作用。在呼吸测定中,PP1 [4-氨基-5-(4-甲基苯基)-7-]大大降低了由成人PMN触发的LPS引发的甲酰甲硫酰基亮氨酰苯丙氨酸(fMLP)触发的O2 -释放。 src激酶抑制剂(叔丁基)吡唑并[3,4-d]嘧啶]达到未治疗的新生儿PMN的水平,其中LPS无法启动。 LPS激活了成年和新生PMN中的src样激酶p59 hck (HCK)和p58 fgr (FGR),但增加了p53 / 56 lyn的激活(LYN)仅适用于成年细胞。在新生儿PMN中,LYN被高度磷酸化,独立于LPS。我们评估了PMNs的亚细胞部分,发现LYN的磷酸化形式主要存在于成年PMNs的Triton可提取的胞质部分中,而在新生细胞中,其主要位于Triton不溶的,颗粒和膜相关部分中。相反,在成年和新生PMNs的胞浆中主要检测到磷酸化的丝裂原活化蛋白激酶ERK1 / 2和p38。这些数据表明LYN在LPS启动调控中的作用。新生儿PMNs的膜颗粒部分中磷酸化LYN的捕获可能导致新生儿细胞对LPS刺激的反应不足。

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