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Lymphotoxin-1β2 and LIGHT Induce Classical and Noncanonical NF-B-Dependent Proinflammatory Gene Expression in Vascular Endothelial Cells¹

Lisa A. Madge^*, Martin S. Kluger, Jordan S. Orange and Michael J. May^2,*

^* Department of Animal Biology and the Mari Lowe Center for Comparative Oncology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104; Department of Dermatology, and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06510; and Division of Allergy and Immunology, The Joseph Stokes Jr. Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Activation of the classical and noncanonical NF-B 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-B-dependent gene expression. We demonstrate that the LTβR ligands LIGHT and LT1β2 activate both NF-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 LT1β2 and not TNF activated the noncanonical pathway. LIGHT and LT1β2 induced the expression of classical NF-B-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 LT1β2 but not TNF in both HUVEC and HDMEC. Using HUVEC retrovirally transduced with dominant negative IB kinase , 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-B pathways and we identify CXCL12 as a bona fide noncanonical NF-B-regulated gene in these cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R01 HL080612 from the National Institutes of Health and by a McCabe Foundation Award (to L.A.M.).

² Address correspondence and reprint requests to Dr. Michael J. May, Department of Animal Biology, Veterinary Hospital Room 200E, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104. E-mail address: maym{at}vet.upenn.edu

³ Abbreviations used in this paper: EC, endothelial cell; HDMEC, human dermal microvascular EC; IKK, IB kinase; LT, lymphotoxin; LTβR, LT-β receptor; NIK, NF-B-inducing kinase; TRAF, TNFR-associated factor HEC, high EC.