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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response
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Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response

机译：人中性粒细胞甲酰基肽受体磷酸化与黏膜炎症反应

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Bacterial/mitochondrial fMLF analogs bind FPR1, driving accumulation/activation of PMN at sites of infection/injury, while promoting wound healing in epithelia. We quantified levels of UFPR1 and TFPR1 in isolated PMN by use of phosphosensitive NFPRb and phosphorylation-independent NFPRa antibodies. UFPR1 and total TFPR were assessed inflamed mucosa, observed in human IBD. In isolated PMN after fMLF stimulation, UFPR1 declined 70% ((EC50)-E-fMLF = 11 +/- 1 nM; t(1/2) = 15 s) and was stable for up to 4 h, whereas TFPR1 changed only slightly. Antagonists (tBoc-FLFLF, CsH) and metabolic inhibitor NaF prevented the fMLF-dependent UFPR1 decrease. Annexin A1 fragment Ac2-26 also induced decreases in UFPR1 (Ac2-26EC50 similar to 3 mu M). Proinflammatory agents (TNF-alpha, LPS), phosphatase inhibitor (okadaic acid), and G-protein activator (MST) modestly increased (EC50)-E-fMLF, 2-to 4-fold, whereas PTX, Ca2+ chelators (EGTA/BAPTA), H2O2, GM-CSF, ENA-78, IL-1RA, and LXA(4) had no effect. Aggregation-inducing PAF, however, strongly inhibited fMLF-stimulated UFPR1 decreases. fMLF-driven PMN also demonstrated decreased UFPR1 after traversing monolayers of cultured intestinal epithelial cells, as did PMN in intestinal mucosal samples, demonstrating active inflammation from UC patients. Total TFPR remained high in PMN within inflamed crypts, migrating through crypt epithelium, and in the lamina propria-adjoining crypts, but UFPR1 was only observed at some peripheral sites on crypt aggregates. Loss of UFPR1 in PMN results from C-terminal S/T phosphorylation. Our results suggest G protein-insensitive, fMLF-dependent FPR1 phosphorylation in isolated suspension PMN, which may manifest in fMLF-driven transmigration and potentially, in actively inflamed tissues, except at minor discrete surface locations of PMN-containing crypt aggregates.
机译：细菌/线粒体fMLF类似物结合FPR1，在感染/损伤部位驱动PMN的积累/激活，同时促进上皮的伤口愈合。我们通过使用磷酸敏感的NFPRb和非磷酸化依赖性NFPRa抗体来定量分离的PMN中UFPR1和TFPR1的水平。在人IBD中观察到UFPR1和总TFPR被评估为发炎的粘膜。在fMLF刺激后的孤立PMN中，UFPR1下降70％（（EC50）-E-fMLF = 11 +/- 1 nM; t（1/2）= 15 s）并稳定长达4 h，而TFPR1仅变化略。拮抗剂（tBoc-FLFLF，CsH）和代谢抑制剂NaF阻止了fMLF依赖性UFPR1的降低。膜联蛋白A1片段Ac2-26也引起UFPR1的减少（Ac2-26EC50类似于3μM）。促炎药（TNF-alpha，LPS），磷酸酶抑制剂（冈田酸）和G蛋白活化剂（MST）适度增加（EC50）-E-fMLF 2至4倍，而PTX，Ca2 +螯合剂（EGTA / BAPTA），H2O2，GM-CSF，ENA-78，IL-1RA和LXA（4）无效。但是，聚集诱导的PAF强烈抑制了fMLF刺激的UFPR1的降低。 fMLF驱动的PMN遍历培养的肠上皮细胞单层后也显示出UFPR1减少，如肠粘膜样品中的PMN一样，证明了UC患者的活动性炎症。在发炎的隐窝内，PMN中的总TFPR仍然很高，并通过隐窝上皮迁移，并且在固有层附近的隐窝中迁移，但仅在隐窝聚集体的某些外围部位观察到UFPR1。 PMN中UFPR1的丢失是由C端S / T磷酸化引起的。我们的结果表明，在分离的悬浮液PMN中，G蛋白不敏感，依赖fMLF的FPR1磷酸化可能会表现在fMLF驱动的迁移过程中，并可能在活跃发炎的组织中出现，除了在含PMN隐窝聚集体的微小离散表面位置。

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