Drayton Danielle L, Bonizzi Giuseppina, Ying Xiaoyan, Liao Shan, Karin Michael, Ruddle Nancy H
Department of Epidemiology and Public Health, Section of Immunobiology, Yale University School of Medicine, 60 College Street, New Haven, CT 06520, USA.
J Immunol. 2004 Nov 15;173(10):6161-8. doi: 10.4049/jimmunol.173.10.6161.
The lymphotoxin (LT) beta 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 LTalphabeta. 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 IKKalpha 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.
淋巴毒素（LT）β受体在次级淋巴器官发生过程中起关键作用，经典和替代NF-κB途径均参与此过程。IKKα是激活替代NF-κB途径的关键分子。然而，其在次级淋巴器官发生中的精确作用和靶基因仍不清楚，尤其是在高内皮微静脉（HEV）方面。在本研究中，我们发现缺乏诱导激酶活性的IKKα（AA）突变小鼠的淋巴结（LN）和鼻相关淋巴组织（NALT）细胞减少，其特征是微观结构和HEV存在明显缺陷。此外，IKKα（AA）淋巴结显示淋巴趋化因子CCL19、CCL21和CXCL13表达降低。IKKα（AA）淋巴结和NALT的HEV外观异常，外周淋巴结地址素（PNAd）表达降低，这是由于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（一种产生PNAd的酶，是LTαβ的靶点）严重减少所致。在本研究中，对LTβ（-/-）小鼠的分析确定GlyCAM-1是另一个LTβ依赖性基因。相比之下，丧失经典NF-κB途径活性但保留替代NF-κB途径活性的TNFRI（-/-）小鼠在LN-HEV中显示相对正常的GlyCAM-1和HEC-6ST表达。此外，在本报告中，证明LTβR在LN和NALT的HEV上显著表达。因此，这些数据揭示了IKKα在LN和NALT发育中的关键作用，确定GlyCAM-1和高内皮细胞磺基转移酶为新的IKKα依赖性靶基因，并表明HEV上的LTβR信号传导可调节HEV特异性基因表达。
