Lymphotoxin-α1β2 and LIGHT Induce Classical and Noncanonical NF-κB-Dependent Proinflammatory Gene Expression in Vascular Endothelial Cells

Abstract

Activation of the classical and noncanonical NF-κB pathways by ligation of the lymphotoxin (LT)-β receptor (LTβR) plays a crucial role in lymphoid organogenesis and in the generation of ectopic lymphoid tissue at sites of chronic inflammation. Within these microenvironments, LTβR signaling regulates the phenotype of the specialized high endothelial cells. However, the direct effects of LTβR ligation on endothelial cells remain unclear. We therefore questioned whether LTβR ligation could directly activate endothelial cells and regulate classical and noncanonical NF-κB-dependent gene expression. We demonstrate that the LTβR ligands LIGHT and LTα1β2 activate both NF-κB pathways in HUVECs and human dermal microvascular endothelial cells (HDMEC). Classical pathway activation was less robust than TNF-induced signaling; however, only LIGHT and LTα1β2 and not TNF activated the noncanonical pathway. LIGHT and LTα1β2 induced the expression of classical NF-κB-dependent genes in HUVEC, including those encoding the adhesion molecules E-selectin, ICAM-1, and VCAM-1. Consistent with this stimulation, LTβR ligation up-regulated T cell adhesion to HUVEC. Furthermore, the homeostatic chemokine CXCL12 was up-regulated by LIGHT and LTα1β2 but not TNF in both HUVEC and HDMEC. Using HUVEC retrovirally transduced with dominant negative IκB kinase α, we demonstrate that CXCL12 expression is regulated by the noncanonical pathway in endothelial cells. Our findings therefore demonstrate that LTβR ligation regulates gene expression in endothelial cells via both NF-κB pathways and we identify CXCL12 as a bona fide noncanonical NF-κB-regulated gene in these cells.

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

“…Of note is that the chemokine SDF-1 has been implicated in the recruitment of T cells to peripheral tissues, and its transcription is regulated in part by LT (32,37). Our data suggest that SDF-1 expression is not a requirement for T cell accumulation into adipose tissue since CD3ϩ cells were more abundant in the LT Ϫ/Ϫ mice, for which we saw no SDF-1 signal.…”

“…The chemokine stromal cell-derived factor-1 (SDF-1) has been implicated in the recruitment of T cells to peripheral tissues, and its transcription is regulated in part by LT (32,37). Therefore, we expected the level of SDF-1 to be reduced in LT Ϫ/Ϫ mice, and this was confirmed by mRNA analyses of mouse epididymal fat tissue.…”

Generalized Wegener's granulomatosis in an immunocompetent adult after cytomegalovirus mononucleosis and bacterial urinary tract infection

“…Cytokine release may have played a role in the case described herein. This patient exhibited extraordinarily high plasma levels of LT␣, a potent endothelial cell activator (13), during HCMV mononucleosis.…”

P2Y2 Receptor-mediated Lymphotoxin-α Secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells

“…Polymorphisms in the LTA gene have been reported to cause a 2-fold increase in induction of cell adhesion molecules in VSMC of human coronary arteries (28). LTA has also been shown to modulate adhe-sion molecule expression in endothelial cells, including ICAM-1 (29,30).…”