Journal
JOURNAL OF IMMUNOLOGY
Volume 180, Issue 5, Pages 3467-3477Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.180.5.3467
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- NHLBI NIH HHS [R01 HL080612-03, R01 HL080612] Funding Source: Medline
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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.
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