IκB kinase complex α kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue
IκB kinase complex α kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue
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DOI：
10.4049/jimmunol.173.10.6161
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发表时间：
2004-11-15
影响因子：
4.4
通讯作者：
Ruddle, NH
中科院分区：
文献类型：
--
作者：
Drayton, DL;Bonizzi, G;Ruddle, NH
光敏素（LT）6受体在次级淋巴器官发生中起关键作用，并且经典和替代NF-κ B途径已经涉及该过程。IKK α是激活NF-κ B旁路途径的关键分子。然而，其确切的作用和靶基因在次级淋巴器官发生仍然未知，特别是关于高内皮微静脉（HEV）。在这项研究中，我们表明，IKK α（AA）突变小鼠，谁缺乏诱导激酶活性，有低细胞淋巴结（LN）和鼻相关淋巴（NALT）组织的特点是显着的缺陷，在微架构和戊型肝炎病毒。此外，IKK α（AA）LN显示淋巴趋化因子CCL 19、CCL 21和CXCL 13表达降低。IKK α（AA）LN-和NALT-HEV外观异常，外周淋巴结地址素（PNAd）表达减少，可通过HEV相关蛋白、糖基化依赖性细胞粘附分子1（GlyCAM-1）和高内皮细胞磺基转移酶（一种PNAd生成酶，是LTalphaB的靶点）的严重减少来解释。在这项研究中，对LT β（-/-）小鼠的分析鉴定出GlyCAM-1是另一种LT β依赖性基因。相比之下，TNFRI-/-小鼠，失去经典的NF-κ B途径活性，但保留替代NF-κ B途径活性，显示相对正常的GlyCAM-1和HEC-6ST在LN-HEV中的表达。此外，在本通信中，证明了LT β R在LN-和NALT-HEV上显著表达。因此，这些数据揭示了IKKa在LN和NALT发展中的关键作用，鉴定了GlyCAM-1和高内皮细胞磺基转移酶作为新的IKKa依赖性靶基因，并表明HEV上的LT β R信号传导可以调节HEV特异性基因表达。
The lymphotoxin (LT) 6 receptor plays a critical role in secondary lymphoid organogenesis and the classical and alternative NF-kappaB pathways have been implicated in this process. IKKalpha is a key molecule for the activation of the alternative NF-kappaB pathway. However, its precise role and target genes in secondary lymphoid organogenesis remain unknown, particularly with regard to high endothelial venules (HEV). In this study, we show that IKKalpha(AA) mutant mice, who lack inducible kinase activity, have hypocellular lymph nodes (LN) and nasal-associated lymphoid (NALT) tissue characterized by marked defects in microarchitecture and HEV. In addition, IKKalpha(AA) LNs showed reduced lymphoid chemokine CCL19, CCL21, and CXCL13 expression. IKKalpha(AA) LN- and NALT-HEV were abnormal in appearance with reduced expression of peripheral node addressin (PNAd) explained by a severe reduction in the HEV-associated proteins, glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1), and high endothelial cell sulfotransferase, a PNAd-generating enzyme that is a target of LTalphaB. In this study, analysis of LTbeta(-/-) mice identifies GlyCAM-1 as another LTbeta-dependent gene. In contrast, TNFRI-/- mice, which lose classical NF-kappaB pathway activity but retain alternative NF-kappaB pathway activity, showed relatively normal GlyCAM-1 and HEC-6ST expression in LN-HEV. In addition, in this communication, it is demonstrated that LTbetaR is prominently expressed on LN- and NALT-HEV. Thus, these data reveal a critical role for IKKa in LN and NALT development, identify GlyCAM-1 and high endothelial cell sulfotransferase as new IKKalpha-dependent target genes, and suggest that LTbetaR signaling on HEV can regulate HEV-specific gene expression.