Regulation of human polymorphonuclear leukocytes functions by the neuropeptide pituitary adenylate cyclase-activating polypeptide after activation of MAPKs
Regulation of human polymorphonuclear leukocytes functions by the neuropeptide pituitary adenylate cyclase-activating polypeptide after activation of MAPKs
复制标题
DOI：
10.4049/jimmunol.173.6.4154
复制
发表时间：
2004-09-15
影响因子：
4.4
通讯作者：
Sariban, E
中科院分区：
文献类型：
--
作者：
Harfi, I;D'Hondt, S;Sariban, E
垂体腺苷酸环化酶激活蛋白（PACAP）的抗炎活性部分是通过对淋巴细胞和巨噬细胞的特异性作用来介导的。这项研究表明，在人多形核中性粒细胞 (PMN) 中，PACAP 充当促炎分子。在 PMN 中，血管肠肽/PACAP 受体 1 (VPAC-1) 是 RT-PCR 发现唯一表达的受体。使用 VPAC-1 Ab，我们发现 VPAC-1 mRNA 被翻译成蛋白质。在 PMN 中，PACAP 会增加 cAMP、三磷酸肌醇代谢物和钙。它激活 MAPK 超家族三个成员中的两个，即 ERK 和应激激活的 MAPK p38。 U73122 是一种磷脂酶 C (PLC) 抑制剂，可抑制 PACAP 诱导的 ERK 激活，而 p38 MAPK 磷酸化不受影响。使用 ERK (PD098059) 和 p38 MAPK (SB203580) 的特定药物抑制剂，我们发现 PACAP 介导的钙增加是 ERK 和 PLC 依赖性的，而不是 p38 依赖性的。 PACAP 引发 fMLP 相关的钙增加；它还引发呼吸爆发的 fMLP 激活以及弹性蛋白酶释放，这最后两个过程依赖于 ERK 和 PLC，而独立于 p38 MAPK。 PACAP 还可增加 CD11b 的膜表达以及乳铁蛋白和金属蛋白酶 9 (MMP-9) 的释放。这些效应是 PLC 依赖性的（CD 11b、乳铁蛋白、MMP-9）、ERK 依赖性的（CD 11b、乳铁蛋白、MMP-9）和 p38 依赖性的（CD11b、乳铁蛋白）。我们得出的结论是，PACAP 是一种直接的 PMN 激活剂，也是一种有效的 PMN 启动剂，需要 PLC、ERK 和 p38 MAPK 活性。
Anti-inflammatory activities of pituitary adenylate cyclase-activating protein (PACAP) are mediated in part through specific effects on lymphocytes and macrophages. This study shows that in human polymorphonuclear neutrophils (PMNs), PACAP acts as a proinflammatory molecule. In PMNs, vaso-intestinal peptide/PACAP receptor 1 (VPAC-1) was the only receptor found to be expressed by RT-PCR. Using VPAC-1 Ab, we found that VPAC-1 mRNA was translated into proteins. In PMNs, PACAP increases cAMP, inositol triphosphate metabolites, and calcium. It activates two of the three members of the MAPK superfamily, the ERK and the stress-activated MAPK p38. U73122, an inhibitor of phospholipase C (PLC), inhibits PACAP-induced ERK activation, whereas p38 MAPK phosphorylation was unaffected. Using specific pharmalogical inhibitors of ERK (PD098059) and p38 MAPK (SB203580), we found that PACAP-mediated calcium increase was ERK and PLC dependent and p38 independent. PACAP primes fMLP-associated calcium increase; it also primes fMLP activation of the respiratory burst as well as elastase release, these last two processes being ERK and PLC dependent and p38 MAPK independent. PACAP also increases membrane expression of CD11b and release of lactoferrin and metallo proteinase-9 (MMP-9). These effects were PLC dependent (CD 11b, lactoferrin, MMP-9), ERK dependent (CD 11b, lactoferrin, MMP-9), and p38 dependent (CD11b, lactoferrin). We conclude that PACAP is a direct PMN activator as well as an effective PMN priming agent that requires PLC, ERK, and p38 MAPK activities.