I kappa B kinase complex alpha kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue.
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.
Drayton
Danielle L
DL
Department of Epidemiology and Public Health, Section of Immunobiology, Yale University School of Medicine, 60 College Street, New Haven, CT 06520, USA.
Bonizzi
Giuseppina
G
Ying
Xiaoyan
X
Liao
Shan
S
Karin
Michael
M
Ruddle
Nancy H
NH
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D004729:Endothelium, Lymphatic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D051550:I-kappa B Kinase; D008024:Ligands; D008198:Lymph Nodes / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053259:Lymphotoxin beta Receptor; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009297:Nasal Mucosa / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology
D018925:Chemokines; D008024:Ligands; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D021122:Protein Subunits; D018124:Receptors, Tumor Necrosis Factor; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse