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 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 alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha), whereas on human dermal microvascular EC (HDMEC) only TNF alpha 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-kappa B binding sequences of the VCAM-1 promoter as a DNA probe. Previous studies have established that these NF-kappa B 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-1 alpha, but not TNF alpha. An upstream VCAM-1 gene regulatory region distinct 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 and promoter.
Emory Skin Diseases Research Center, Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA.
J
J
Gille
R A
RA
Swerlick
T J
TJ
Lawley
S W
SW
Caughman
D001483:Base Sequence; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008833:Microcirculation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012867:Skin / Q000098:blood supply*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
D007375:Interleukin-1; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1