ESE-1 is a novel transcriptional mediator of inflammation that interacts with NF-kappa B to regulate the inducible nitric-oxide synthase gene.
Inflammation is a hallmark of several vascular diseases. The nuclear factor kappaB (NF-kappaB) transcription factors are dimeric proteins involved in the activation of a large number of genes in response to inflammatory stimuli. We report the involvement of a novel member of the ETS transcription factor, ESE-1, in mediating vascular inflammation. ESE-1 is induced in response to inflammatory cytokines and lipopolysaccharide in vascular smooth muscle cells, endothelial cells, and cells of the monocyte-macrophage lineage. This induction occurs within hours of stimulation and is mediated by NF-kappaB transactivation of the ESE-1 promoter. We have identified the inducible form of nitric-oxide synthase (NOS2) as a putative target for ESE-1. ESE-1 can bind to the p50 subunit of NF-kappaB, and cotransfection of ESE-1 with the p50 and p65 subunits of NF-kappaB synergistically enhances transactivation of the NOS2 promoter by ESE-1. An ESE-1-binding site within the NOS2 promoter has been identified, the site-directed mutagenesis of which completely abolishes the ability of ESE-1 to transactivate the NOS2 promoter. Finally, in a mouse model of endotoxemia, associated with acute vascular inflammation, ESE-1 is strongly expressed in vascular endothelium and smooth muscle cells. In summary, ESE-1 represents a novel mediator of vascular inflammation.
Rudders
S
S
Cardiology Division, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Gaspar
J
J
Madore
R
R
Voland
C
C
Grall
F
F
Patel
A
A
Pellacani
A
A
Perrella
M A
MA
Libermann
T A
TA
Oettgen
P
P
D001665:Binding Sites; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D050863:Synaptotagmin I; D050857:Synaptotagmins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014652:Vascular Diseases / Q000378:metabolism
D002135:Calcium-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D050863:Synaptotagmin I; D015534:Trans-Activators; D014157:Transcription Factors; D050857:Synaptotagmins; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II