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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1421-1429.)
© 1999 American Heart Association, Inc.

Vascular Biology

Stat6 Activation Is Essential for Interleukin-4 Induction of P-Selectin Transcription in Human Umbilical Vein Endothelial Cells

Yeesim Khew-Goodall; Carol Wadham; Brian N. Stein; Jennifer R. Gamble; Mathew A. Vadas

From the Hanson Centre for Cancer Research, Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, Australia.

Correspondence to Yeesim Khew-Goodall, PhD, Hanson Centre for Cancer Research, Division of Human Immunology, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000, Australia. E-mail yeesim.khew-goodall{at}imvs.sa.gov.au

Abstract—Chronic upregulation of P-selectin expression on the surface of the endothelium has been observed in and likely contributes to a number of chronic inflammatory diseases, including atherosclerosis. Agonists of P-selectin expression fall into 2 categories: those that induce a very rapid, transient increase, lasting only hours, and those that induce prolonged upregulation lasting days. It is the latter group, which includes interleukin-4 (IL-4), that is likely to be a mediator of chronic P-selectin upregulation. The increase in P-selectin expression induced by IL-4 results from increased transcriptional activation of the P-selectin gene. The aim of this study was to deduce the postreceptor signaling pathway(s) giving rise to the prolonged increase in P-selectin expression induced by IL-4. We demonstrate the existence of 2 functional signal transducer and activator of transcription 6 (Stat6) binding sites on the P-selectin promoter and further demonstrate, by functional analysis of the P-selectin promoter, that binding of activated Stat6 to at least 1 site is essential for IL-4-induction of P-selectin transcription. Site 1 (nucleotide[nt] -142) bound Stat6 with a higher affinity than did site 2 (nt -229), and this difference was reflected functionally as constructs in which only site 1 was functional showed full IL-4 inducibility, whereas constructs in which only site 2 was functional showed only 40% of maximal IL-4 inducibility. IL-4 also induced prolonged activation of Stat6, which was contingent on the continuous presence of IL-4. The sustained activation of Stat6 induced by IL-4 is likely to be a key factor leading to the prolonged activation of the P-selectin promoter, thereby resulting in prolonged P-selectin upregulation.

Key Words: P-selectin • interleukin-4 • Stat6 • inflammation • chronic effects

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