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首页> 外文期刊>Biochemical Pharmacology >Involvement of cyclic AMP generation in the inhibition of respiratory burst by 2-phenyl-4-quinolone (YT-1) in rat neutrophils.
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Involvement of cyclic AMP generation in the inhibition of respiratory burst by 2-phenyl-4-quinolone (YT-1) in rat neutrophils.

机译：环状AMP产生参与大鼠中性粒细胞的2-苯基-4-喹诺酮（YT-1）抑制呼吸爆发。

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摘要

The inhibitory effect of 2-phenyl-4-quinolone (YT-1) on respiratory burst in rat neutrophils was investigated, and the underlying mechanism of action was assessed. YT-1 caused a concentration-dependent inhibition of the rate of O2.- release from rat neutrophils in response to formylmethionyl-leucyl-phenylalanine (fMLP), but not to phorbol 12-myristate 13-acetate (PMA), with an IC50 value of 60.7+/-8.2 microM. A comparable effect was also demonstrated in the inhibition of O2 consumption. Unlike superoxide dismutase, YT-1 had no effect on O2.- generation in the xanthine-xanthine oxidase system and during dihydroxyfumaric acid autoxidation. The fMLP-induced inositol trisphosphate (IP3) formation was unaffected by YT-1. In addition, YT-1 did not affect the initial spike of [Ca2+]i, but it accelerated the rate of [Ca2+]i decline in cells in response to fMLP. YT-1 was found to have little effect on the activity of neutrophil cytosolic protein kinase C (PKC). YT-1 increased the cellular cyclic AMP level, while having no effect on the cyclic GMP level. In addition, YT-1 increased neutrophil cytosolic protein kinase A (PKA) activity, but had no direct effect on the enzyme activity of pure porcine heart PKA. When neutrophils were treated with (8R,9S,11S)-(-)-9-hydroxy-9-hexoxycarbonyl-8-methyl-2,3,9,10-tetra hydro-8,11-epoxy- 1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinde n-1-one, (KT 5720), a PKA inhibitor, the inhibition of O2.- generation by YT-1, as well as by prostaglandin E1 (PGE1) and dibutyryl cyclic AMP, was attenuated effectively. YT-1 did not activate the adenylate cyclase associated with neutrophil particulate fraction but inhibited the cytosolic phosphodiesterase (PDE) activity in a concentration-dependent manner. Neutrophils treated with YT-1 had a more pronounced increase in cellular cyclic AMP level by PGE1. Moreover, the ability of PGE1 to inhibit the respiratory burst in neutrophils was greatly enhanced by YT-1. These results suggest that the increase in cellular cyclic AMP levels by YT-1 through the inhibition of PDE (probably PDE4 isoenzyme) activity is involved in its inhibition of fMLP-induced respiratory burst in rat neutrophils.
机译：研究了2-苯基-4-喹诺酮（YT-1）对大鼠中性粒细胞呼吸爆发的抑制作用，并评估了其潜在的作用机制。 YT-1对大鼠中性粒细胞的O2-释放速率具有浓度依赖性抑制作用，以响应甲酰甲硫基-亮氨酰-苯丙氨酸（fMLP），但不响应佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA），IC50值为60.7 +/- 8.2 microM。在抑制氧气消耗方面也显示了可比的效果。与超氧化物歧化酶不同，YT-1对黄嘌呤-黄嘌呤氧化酶系统和二羟基富马酸自氧化过程中的O2.-生成没有影响。 fMLP诱导的肌醇三磷酸（IP3）的形成不受YT-1的影响。此外，YT-1不会影响[Ca2 +] i的初始尖峰，但会加快细胞响应fMLP引起的[Ca2 +] i下降的速率。发现YT-1对嗜中性粒细胞胞质蛋白激酶C（PKC）的活性影响很小。 YT-1增加了细胞循环AMP的水平，而对循环GMP的水平没有影响。此外，YT-1增加中性粒细胞胞浆蛋白激酶A（PKA）的活性，但对纯猪心脏PKA的酶活性没有直接影响。用（8R，9S，11S）-（-）-9-羟基-9-己氧羰基-8-甲基-2,3,9,10-四氢-8,11-环氧-1H，8H处理中性粒细胞时， PKA抑制剂11H-2,7b，11a-三氮杂二苯并[a，g]环辛三烯n-1-one（KT 5720），YT-1和前列腺素E1（PGE1）和二丁酰环AMP被有效减弱。 YT-1不会激活与嗜中性粒细胞颗粒级分相关的腺苷酸环化酶，但会以浓度依赖的方式抑制胞质磷酸二酯酶（PDE）的活性。用YT-1处理的嗜中性粒细胞通过PGE1具有更明显的细胞环AMP含量增加。此外，YT-1大大增强了PGE1抑制中性粒细胞呼吸爆发的能力。这些结果表明，YT-1通过抑制PDE（可能是PDE4同工酶）活性而增加了细胞环AMP的水平，这与抑制fMLP诱导的大鼠中性粒细胞呼吸爆发有关。

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