Differential regulation of vascular cell adhesion molecule-1 gene transcription by tumor necrosis factor α and interleukin-1α in dermal microvascular endothelial cells

Abstract

As part of the inflammatory response, the localization of leukocytes depends to an important degree on cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells (EC). We have previously shown that VCAM-1 expression is induced on human umbilical vein EC (HUVEC) by both tumor necrosis factor α (TNFα) and interleukin-1α (IL- 1α), whereas on human dermal microvascular EC (HDMEC) only TNFα results in VCAM-1 expression. To explore molecular mechanisms responsible for these contrasting patterns of VCAM-1 induction in HUVEC versus HDMEC, we performed transcriptional activation studies with VCAM-1-based reporter constructs and in vitro binding assays using two adjacent NF-κB binding sequences of the VCAM-1 promoter as a DNA probe. Previous studies have established that these NF-κB motifs are required for cytokine-induced VCAM-1 transcription, and may further mediate cell-specific VCAM-1 gene activation by cytokines. The findings reported here demonstrate a significant HDMEC-specific attenuation of VCAM-1 gene transcription in response to IL-1α, but not TNFα. An upstream VCAM-1 gene regulatory region distinct from the NF-κB sites appears to function as an IL-1α-mediated transcriptional repressor within HDMEC. This repressor region conveys IL-1α-dependent, but not TNFα-dependent, inhibition of transcription driven by a heterologous cytokine response element and promoter.