doi: 10.1161/hq1001.097027
© 2001 American Heart Association, Inc.
Vascular Biology |
Increased Transcription of IL-8 in Endothelial Cells Is Differentially Regulated by TNF-
and Oxidized Phospholipids
From the Department of Pathology (M.Y., D.K.V., J.A.B.), the Division of Cardiology, Department of Medicine (M.Y., D.K.V., J.A.B., S.T.R.), and the Department of Molecular and Medical Pharmacology (S.T.R.), University of California, Los Angeles; the Department of Vascular Biology and Thrombosis Research (N.L., R.d.M.), University of Vienna, Vienna, Austria; and the Department of Molecular Preventive Medicine (N.O., K.M.), University of Tokyo, Tokyo, Japan.
Correspondence to Judith A. Berliner, MD, University of California, Los Angeles, Department of Pathology and Medicine, 47-123 Center of Health Science, 650 Charles E. Young South, Los Angeles, CA 90095. E-mail jberliner{at}mednet.ucla.edu
Abstract—— Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) upregulates a spectrum of inflammatory cytokines and adhesion molecules different from those induced by classic inflammatory mediators such as tumor necrosis factor-
(TNF-) or lipopolysaccharide. Interestingly, Ox-PAPC also induces the expression of a set of proteins similar to those induced by TNF- or lipopolysaccharide, which include the chemokines monocyte chemotactic protein-1 (MCP-1) and interleukin (IL)-8. To elucidate the molecular mechanisms of Ox-PAPC-induced gene expression and to determine whether Ox-PAPC and other inflammatory mediators such as TNF- utilize common signaling pathways, we examined the transcriptional regulation of IL-8 by Ox-PAPC and TNF- in human aortic endothelial cells. Both Ox-PAPC and TNF- induced the expression of IL-8 mRNA in a dose-dependent fashion; however, the kinetics of IL-8 mRNA accumulation between the 2 ligands differed. Ox-PAPC-induced IL-8 mRNA was seen as early as 30 minutes, peaked between 4 and 8 hours, and decreased substantially by 24 hours. In contrast, TNF--induced IL-8 mRNA synthesis was elevated at 30 minutes, peaked at 2 hours, and reached basal/undetectable levels by 6 hours. Actinomycin D experiments suggested that both Ox-PAPC and TNF- regulate the expression of IL-8 at the transcriptional level. Furthermore, the half-life of IL-8 mRNA for both ligands was similar (<30 minutes), suggesting that mRNA stability was not responsible for the differences in the kinetics of IL-8 accumulation between the 2 ligands. Transient transfection studies with reporter constructs containing 1.48 kb of the IL-8 promoter identified an Ox-PAPC-specific response region between -133 and -1481 bp of the IL-8 promoter. In contrast, TNF- activation of the IL-8 promoter was mediated almost entirely through the nuclear factor-
B and activation protein-1 response elements present between -70 and -133 bp of the IL-8 promoter. Thus, although Ox-PAPC and TNF- both induced IL-8 synthesis, our data suggest that the 2 ligands utilize different mechanisms in the regulation of IL-8 transcription.
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