Zernecke A, Weber K S, Weber C
Institute for Prevention of Cardiovascular Disease, Ludwig-Maximilians Universität München, D-80336 Munich, Germany.
Am J Physiol Cell Physiol. 2001 Dec;281(6):C1881-8. doi: 10.1152/ajpcell.2001.281.6.C1881.
The activation of nuclear factor-kappaB (NF-kappaB) is required for the induction of many of the adhesion molecules and chemokines involved in the inflammatory leukocyte recruitment to the kidney. Here we studied the effects of NF-kappaB inhibition on the machinery crucial for monocyte infiltration of the glomerulus during inflammation. In mesangial cells (MC), the protease inhibitors MG-132 and N-alpha-tosyl-L-lysine chloromethyl ketone or adenoviral overexpression of IkappaB-alpha prevented the complete IkappaB-alpha degradation following tumor necrosis factor-alpha (TNF-alpha) stimulation. This resulted in a marked inhibition of TNF-alpha-induced expression of mRNA and protein for the immunoglobulin molecules intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and the chemokines growth-related oncogene-alpha, monocyte chemoattractant protein-1, interleukin-8, or fractalkine in MC. Finally, the inhibition of IkappaB-alpha degradation or IkappaB-alpha overexpression suppressed the chemokine-induced transendothelial monocyte chemotaxis toward MC and the chemokine-triggered firm adhesion of monocytic cells to MC. The inhibition of NF-kappaB by pharmacological intervention or gene transfer may present a multimodal approach to control the machinery propagating inflammatory recruitment of monocytes during glomerular disease.
炎症性白细胞募集到肾脏所涉及的许多黏附分子和趋化因子的诱导需要核因子-κB（NF-κB）的激活。在此，我们研究了NF-κB抑制对炎症期间单核细胞浸润肾小球的关键机制的影响。在系膜细胞（MC）中，蛋白酶抑制剂MG-132和N-α-甲苯磺酰-L-赖氨酸氯甲基酮或IkappaB-α的腺病毒过表达可防止肿瘤坏死因子-α（TNF-α）刺激后IkappaB-α的完全降解。这导致MC中TNF-α诱导的免疫球蛋白分子细胞间黏附分子-1和血管细胞黏附分子-1以及趋化因子生长相关癌基因-α、单核细胞趋化蛋白-1、白细胞介素-8或fractalkine的mRNA和蛋白表达受到显著抑制。最后，IkappaB-α降解的抑制或IkappaB-α过表达抑制了趋化因子诱导的单核细胞跨内皮细胞向MC的趋化作用以及趋化因子触发的单核细胞与MC的牢固黏附。通过药物干预或基因转移抑制NF-κB可能是一种多模式方法，用于控制肾小球疾病期间单核细胞炎症募集的传播机制。
