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Published online before print June 3, 2003

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(Journal of Leukocyte Biology. 2003;74:420-427.)
© 2003 by Society for Leukocyte Biology

IL-4 primes human endothelial cells for secondary responses to histamine

Tom Wierzbicki^*, Shehzad M. Iqbal, Susan L. Cuvelier, Geneve Awong, Lee Anne Tibbles and Kamala D. Patel^*,,1

Departments of
Physiology and Biophysics and
^* Biochemistry and Molecular Biology. Immunology Research Group, University of Calgary, Alberta, Canada

¹Correspondence: Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. E-mail: kpatel{at}ucalgary.ca

Interleukin-4 (IL-4) is a multifunctional cytokine, which is involved in numerous disease states, including atopic asthma. IL-4 not only induces direct responses in cells but can also prime for secondary responses to stimuli. Little is known about the priming effects of IL-4 on endothelial cells; therefore, we chose to examine the ability of IL-4 to prime endothelial cells for platelet-activating factor (PAF) synthesis and prostaglandin E₂ (PGE₂) release. IL-4 alone did not enhance PAF synthesis or PGE₂ release; however, pretreatment with IL-4 primed for PAF synthesis and PGE₂ release in response to subsequent stimulation with histamine. In contrast, tumor necrosis factor (TNF-), oncostatin M (OSM), and IL-1ß did not prime endothelial cells for PAF synthesis in response to histamine. The priming effects of IL-4 occurred without any detectable changes in the requirement for signaling pathways upstream of PGE₂ release. IL-4 treatment increased the expression of mRNA for histamine receptor 1 (HR1) and shifted the inhibition curve for pyrilamine, a specific HR1 antagonist. In addition, the dose-response curve for histamine-induced elevations in intracellular calcium was shifted following IL-4 stimulation. Together, these data indicate that HR1 is up-regulated in IL-4-stimulated human umbilical vein endothelial cells (HUVEC) and suggest that this up-regulation may contribute to the enhanced responsiveness of IL-4-stimulated HUVEC to histamine.

Key Words: G protein-coupled receptor • HUVEC • platelet-activating factor • prostaglandin E₂

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