Lymphotoxin-α1β2 and LIGHT induce classical and noncanonical NF-κB-dependent proinflammatory gene expression in vascular endothelial cells
Lymphotoxin-α1β2 and LIGHT induce classical and noncanonical NF-κB-dependent proinflammatory gene expression in vascular endothelial cells
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DOI：
10.4049/jimmunol.180.5.3467
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
May, Michael J.
中科院分区：
文献类型：
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作者：
Madge, Lisa A.;Kluger, Martin S.;May, Michael J.
通过连接淋巴毒素(LT)-β受体(LT-βR)激活经典和非典型的NF-kappa B通路，在淋巴器官发生和慢性炎症部位异位淋巴组织的产生中起着至关重要的作用。在这些微环境中，LTβR信号调节特化的高内皮细胞的表型。然而，LTβR结扎对内皮细胞的直接影响尚不清楚。因此，我们质疑LTβR结扎是否可以直接激活内皮细胞，调节经典的和非典型的核因子-kappa B依赖的基因表达。我们证明LTβR配体LIGH和LTα1β2激活HUVEC和人真皮微血管内皮细胞(HDMEC)中的核因子-kappa B通路。经典途径的激活没有肿瘤坏死因子诱导的信号那么强烈；然而，只有LIGH和LTα1β2而不是肿瘤坏死因子激活了非典型途径。LIGH和LTα1β2诱导HUVEC表达经典的NF-kappa B依赖基因，包括那些编码黏附分子E-选择素、ICAM-1和VCAM-1的基因。与此刺激相一致的是，LTβR结扎可上调T细胞与HUVEC的黏附。此外，在HUVEC和HDMEC中，光和LTα1β2上调动态平衡趋化因子CXCL12，但不上调肿瘤坏死因子。利用逆转录病毒转导显性阴性I kappa B激酶α的HUVEC，我们证明了CXCL12的表达是由内皮细胞中的非规范途径调节的。因此，我们的研究结果表明，LTβR连接通过两条NF-kappa B途径调节内皮细胞的基因表达，我们发现CXCL12在这些细胞中是一个真正的非规范的NF-kappa B调节基因。
Activation of the classical and noncanonical NF-kappa B pathways by ligation of the lymphotoxin (LT)-beta receptor (LT beta R) plays a crucial role in lymphoid organogenesis and in the generation of ectopic lymphoid tissue at sites of chronic inflammation. Within these microenvironments, LT beta R signaling regulates the phenotype of the specialized high endothelial cells. However, the direct effects of LT beta R ligation on endothelial cells remain unclear. We therefore questioned whether LT beta R ligation could directly activate endothelial cells and regulate classical and noncanonical NF-kappa B-dependent gene expression. We demonstrate that the LT beta R ligands LIGHT and LT alpha 1 beta 2 activate both NF-kappa B pathways in HUVECs and human dermal microvascular endothelial cells (HDMEC). Classical pathway activation was less robust than TNF-induced signaling; however, only LIGHT and LT alpha 1 beta 2 and not TNF activated the noncanonical pathway. LIGHT and LT alpha 1 beta 2 induced the expression of classical NF-kappa B-dependent genes in HUVEC, including those encoding the adhesion molecules E-selectin, ICAM-1, and VCAM-1. Consistent with this stimulation, LT beta R ligation up-regulated T cell adhesion to HUVEC. Furthermore, the homeostatic chemokine CXCL12 was up-regulated by LIGHT and LT alpha 1 beta 2 but not TNF in both HUVEC and HDMEC. Using HUVEC retrovirally transduced with dominant negative I kappa B kinase alpha, we demonstrate that CXCL12 expression is regulated by the noncanonical pathway in endothelial cells. Our findings therefore demonstrate that LT beta R ligation regulates gene expression in endothelial cells via both NF-kappa B pathways and we identify CXCL12 as a bona fide noncanonical NF-kappa B-regulated gene in these cells.