We recently reported that the single nucleotide polymorphisms of the lymphotoxin-(LT)alpha gene, a member of the tumor necrosis factor (TNF) family, are closely related to acute myocardial infarction; however, the precise mechanism of LT alpha. signaling in atherogenesis remains unclear. We investigated the role of LT alpha 3, a secreted homotrimer of LT alpha, in monocyte-endothelial cell adhesion using cultured human umbilical vein endothelial cells (HUVEC). We found that LT alpha 3 induced cell adhesion molecules and activated NF-kappa B p50 and p65. LT alpha 3 also induced phosphorylation of Akt, phosphorylation and degradation of I kappa B, nuclear translocation of p65, and increased adhesion of THP1 menocytes to HUVEC. These effects were mediated by TNF receptor (TNFR) I and attenuated by the phosphatidylinositol triphosphate-kinase (PI3K) inhibitors LY294002 and Wortmannin. Thus, LT alpha 3 mediates the monocyte-endothelial interaction via the classical NF-kappa B pathway following TNFR I/PI3K activation, indicating it may play a role in the development of coronary artery disease. (c) 2008 Elsevier Inc. All rights reserved.