Bacillus anthracis-derived edema toxin (ET) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway.
Bacillus anthracis-derived edema toxin (ET) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway.
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DOI：
10.1186/1471-2180-12-2
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发表时间：
2012-01-09
期刊：
影响因子：
4.2
通讯作者：
Goldblum SE
中科院分区：
文献类型：
--
作者：
Nguyen C;Feng C;Zhan M;Cross AS;Goldblum SE
吸入性炭疽病患者的一个常见发现是，面对大量循环中的中性粒细胞，感染组织中缺乏多形核白细胞(PMN)。炭疽的一个主要毒力决定因素是水肿性毒素(ET)，它是由生物体产生的两种蛋白质--水肿素(EF)和保护性抗原(PA)--结合而成的。由于腺苷环化酶的产物cAMP可以增强内皮屏障的完整性，我们询问ET是否可以通过关闭PMN所经过的细胞旁途径来减少PMN向组织中的外渗。人肺微血管内皮细胞S(HMVEC-L)经ET处理后，白细胞介素8(IL-8)诱导的中性粒细胞(PMN)跨内皮迁移能力降低，最大可减少近60%。这种效果需要EF和PA的同时存在。相反，在无EC的系统中，ET并没有减少PMN的趋化作用。与中浓度对照组相比，亚汇合流HMVEC-LS可使经内皮细胞14C-白蛋白流量减少约50%。ET与肿瘤坏死因子-α或细菌脂多糖联合应用，均可减弱由任一种药物单独引起的内皮14C-白蛋白流量的增加。ET对透射电子显微镜的抑制作用与蛋白激酶A(PKA)活性的升高相平行，但不能被H-89或KT-5720抑制PKA所阻断。最后，我们无法用Forskolin或3-异丁基-1-甲基黄嘌呤复制ET效应，这两种药物都能增加cAMP。我们的结论是，ET降低IL-8驱动的PMN跨血管内皮细胞-L单层的瞬变速度，而不依赖于cAMP/PKA活性。
A common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (PMNs) in infected tissues in the face of abundant circulating PMNs. A major virulence determinant of anthrax is edema toxin (ET), which is formed by the combination of two proteins produced by the organism, edema factor (EF), which is an adenyl cyclase, and protective antigen (PA). Since cAMP, a product of adenyl cyclase, is known to enhance endothelial barrier integrity, we asked whether ET might decrease extravasation of PMNs into tissues through closure of the paracellular pathway through which PMNs traverse. Pretreatment of human microvascular endothelial cell(EC)s of the lung (HMVEC-L) with ET decreased interleukin (IL)-8-driven transendothelial migration (TEM) of PMNs with a maximal reduction of nearly 60%. This effect required the presence of both EF and PA. Conversely, ET did not diminish PMN chemotaxis in an EC-free system. Pretreatment of subconfluent HMVEC-Ls decreased transendothelial 14 C-albumin flux by ~ 50% compared to medium controls. Coadministration of ET with either tumor necrosis factor-α or bacterial lipopolysaccharide, each at 100 ng/mL, attenuated the increase of transendothelial 14 C-albumin flux caused by either agent alone. The inhibitory effect of ET on TEM paralleled increases in protein kinase A (PKA) activity, but could not be blocked by inhibition of PKA with either H-89 or KT-5720. Finally, we were unable to replicate the ET effect with either forskolin or 3-isobutyl-1-methylxanthine, two agents known to increase cAMP. We conclude that ET decreases IL-8-driven TEM of PMNs across HMVEC-L monolayers independent of cAMP/PKA activity.
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影响因子：
56.9
作者：
Kawasaki, H;Springett, GM;Graybiel, AM
通讯作者：
Graybiel, AM
影响因子：
5.3
作者：
Fukuhara, S;Sakurai, A;Mochizuki, N
通讯作者：
Mochizuki, N
影响因子：
3.1
作者：
HOOVER, DL;FRIEDLANDER, AM;CROSS, AS
通讯作者：
CROSS, AS
影响因子：
4.4
作者：
Crawford, Matthew A.;Aylott, Caroline V.;Bokoch, Gary M.
通讯作者：
Bokoch, Gary M.
影响因子：
5.6
作者：
Bogatcheva, Natalia V.;Zemskova, Marina A.;Kovalenkov, Yevgeniy;Poirier, Christophe;Verin, Alexander D.
通讯作者：
Verin, Alexander D.