DIFFERENTIAL REGULATION OF VASCULAR CELL-ADHESION MOLECULE-1 GENE-TRANSCRIPTION BY TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-ALPHA IN DERMAL MICROVASCULAR ENDOTHELIAL-CELLS

As part of the inflammatory response, the localization of leukocytes d epends to an important degree on cytokine-induced expression of vascul ar cell adhesion molecule-1 (VCAM-1) on endothelial cells (EC). We hav e previously shown that VCAM-1 expression is induced on human umbilica l vein EC (HUVEC) by both tumor necrosis factor alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha), whereas on human dermal microvascula r EC (HDMEC) only TNF alpha results in VCAM-1 expression. To explore m olecular mechanisms responsible for these contrasting patterns of VCAM -1 induction in HUVEC versus HDMEC, we performed transcriptional activ ation studies with VCAM-1-based reporter constructs and in vitro bindi ng assays using two adjacent NF-kappa B binding sequences of the VCAM- 1 promoter as a DNA probe. Previous studies have established that thes e NF-kappa B motifs are required for cytokine-induced VCAM-1 transcrip tion, 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-1 alpha, but not TNF alpha. An upstream VCAM-1 gene regulatory region di stinct from the NF-kappa B sites appears to function as an IL-1 alpha- mediated transcriptional repressor within HDMEC. This repressor region conveys IL-1 alpha-dependent, but not TNF alpha-dependent, inhibition of transcription driven by a heterologous cytokine response element a nd promoter. (C) 1996 by The American Society of Hematology.