Inhibition of neutrophil and monocyte recruitment by endogenous and exogenous lipocortin 1
Inhibition of neutrophil and monocyte recruitment by endogenous and exogenous lipocortin 1
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DOI：
10.1038/sj.bjp.0701029
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发表时间：
1997-03-01
影响因子：
7.3
通讯作者：
Perretti, M
中科院分区：
文献类型：
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作者：
Getting, SJ;Flower, RJ;Perretti, M
1通过使用几种针对脂皮质素1或脂皮质素1衍生的N-末端肽（肽Ac 2 -26）产生的中和多克隆抗体，研究了内源性脂皮质素1在地塞米松（Dex）对急性炎症体内模型中单核细胞募集施加的抗迁移作用中所起的作用。还测试了肽Ac 2 -26抑制单核细胞和多形核白细胞（PMN）募集的功效。注射酵母聚糖A（1 mg）在小鼠腹膜腔中产生时间依赖性细胞积累，其遵循急性炎症的典型特征：中性粒细胞内流在酵母多糖作用后4 h达到最大（每只小鼠15至20 × 10（6）个细胞），随后是单核细胞的积累，在24小时时间点达到峰值（每只小鼠10至15 × 10（6）个细胞）。3 Dex给药小鼠减少酵母多糖诱导的4 h PMN浸润和24 h单核细胞蓄积，具有相似的功效：在每只小鼠30 μ g的剂量下（类似于1 mg/kg，皮下（s.c.）），实现了对两种细胞类型募集的约50%的抑制。每只小鼠皮下注射100 μ g（相当于3 mg kg（-1））后，对中性粒细胞和单核细胞募集的最大抑制分别为64%和67%。4 Dex（30 μ g s.c.）在用非免疫绵羊血清（50 μ l s.c.）处理的小鼠中，抑制单核细胞（53%）和PMN（69%）响应酵母聚糖应用的积累。相比之下，类固醇在减少已经针对全长人重组脂皮质素1（血清LCS 3）或针对脂皮质素1 N-末端肽被动免疫的小鼠中的细胞积累方面不再具有活性。在给药后24小时评估时产生显著的白细胞减少症。这是伴随着减少60%的4小时-中性粒细胞流入，并减少27%的24小时-单核细胞的积累，酵母多糖管理后测量。在长春碱处理的小鼠中，Dex对单核细胞募集的抑制作用没有显著改变，在溶媒和长春碱处理的小鼠中，在30 μ g Dex剂量下计算的抑制率为36%和57%，在100 μ g Dex剂量下计算的抑制率为70%和60%，用肽Ac 2 -26处理小鼠在酵母聚糖后4小时剂量依赖性地减弱PMN流入，在100 μ g/小鼠时具有显著效果（45%的抑制，n = 9，P
1 The role played by endogenous lipocortin 1 in the anti-migratory action exerted by dexamethasone (Dex) on monocyte recruitment in an in vivo model of acute inflammation was investigated by use of several neutralizing polyclonal antibodies raised against lipocortin 1 or a lipocortin 1-derived N-terminus peptide (peptide Ac2-26). The efficacy of peptide Ac2-26 in inhibiting monocyte and polymorphonuclear leucocyte (PMN) recruitment was also tested.2 Intraperitoneal (i.p.) injection of zymosan A (1 mg) produced a time-dependent cell accumulation into mouse peritoneal cavities which followed a typical profile of acute inflammation: PMN influx was maximal at 4 h post-zymosan (between 15 and 20 x 10(6) cells per mouse), and this was followed by an accumulation of monocytes which peaked at the 24 h time-point (between 10 and 15 x 10(6) cells per mouse).3 Dex administration to mice reduced zymosan-induced 4 h PMN infiltration and 24 h monocyte accumulation with similar efficacy: approximately 50% of inhibition of recruitment of both cell types was achieved at the dose of 30 mu g per mouse (similar to 1 mg kg(-1), subcutaneously (s.c.)). Maximal inhibitions of 64% and 67% on PMN and monocyte recruitment, respectively, were measured after a dose of 100 mu g per mouse (similar to 3 mg kg(-1), s.c.).4 Dex (30 mu g s.c.) inhibited monocyte (53%) and PMN (69%) accumulation in response to zymosan application in mice which had been treated with a non-immune sheep serum (50 mu l s.c.). In contrast, the steroid was no longer active in reducing cell accumulation in mice which had been passively immunized against full length human recombinant lipocortin 1 (serum LCS3), or against lipocortin 1 N-terminus peptide.5 Treatment of mice with vinblastine (1 mg kg(-1), intravenously (i.v.)) produced a remarkable leucopenia as assessed 24 h after administration. This was accompanied by a 60% reduction in 4 h-PMN influx, and by a 27% reduction in 24 h-monocyte accumulation, measured after zymosan administration. The inhibitory effect of Dex on monocyte recruitment was not significantly modified in vinblastine-treated mice, with 36% and 57% of inhibition calculated at the dose of 30 mu g Dex, and 70% and 60% of inhibition at 100 mu g Dex, in vehicle- and vinblastine-treated mice, respectively.6 Treatment of mice with peptide Ac2-26 dose-dependently attenuated PMN influx at 4 h post-zymosan with a significant effect at 100 mu g per mouse (45% of inhibition, n = 9, P