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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1291-1299
Endothelin-1-Induced Interleukin-8 Production in Human Brain-Derived
Endothelial Cells Is Mediated by the Protein Kinase C and Protein
Tyrosine Kinase Pathways
R. Zidovetzki,
P. Chen,
M. Chen, and
F.M. Hofman
From the Departments of Biology and Neuroscience, University of
California, Riverside, CA; and the Department of Pathology, University
of Southern California School of Medicine, Los Angeles, CA.
We have previously demonstrated that endothelin-1 (Et-1) induces
human central nervous system-derived endothelial cells (CNS-EC) to
produce and secrete the chemokine interleukin 8 (IL-8). In the present
study, we use specific inhibitors and activators to elucidate the
signal transduction pathways involved in this process. Et-1-induced
IL-8 production was blocked by ETA receptor antagonist BQ610, but not by ETB receptor antagonist BQ788,
demonstrating that CNS-EC activation is initiated by Et-1 binding to
the ETA receptor. IL-8 mRNA expression is blocked by the
protein kinase C inhibitor bisindolylmaleimide or protein tyrosine
kinase inhibitors, genestein and geldanamycin, establishing the
involvement of the protein kinase C and protein tyrosine kinase
pathways in the activation process. The transcription factor, NF- B,
is involved in Et-1 activation as determined by specific inhibitors of
translocation and direct analysis of DNA-binding proteins. Neither
inhibition nor activation of cAMP-dependent protein kinase affected
IL-8 production in the absence or presence of Et-1. Similarly, no
effect was observed upon inhibition of protein phosphatases by okadaic acid. Thus, the signal transduction process induced by Et-1 in CNS-EC,
leading to increased mRNA IL-8 expression, is initiated by Et-1 binding
to ETA receptor followed by subsequent activation of
protein kinase C, protein tyrosine kinase, and NF-B. Because increased expression of Et-1 is associated with hypertension and stroke
and IL-8 is likely to be involved in the accumulation of neutrophils
causing tissue damage in ischemic/reperfusion injury, identification of
the mechanism involved in the Et-1-induced increase in IL-8 production
may have significant therapeutic value.
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