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Intracellular signaling pathways involved in the release of IL-4 and VEGF from human keratinocytes by activation of kinin B1 receptor: functional relevance to angiogenesis

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Abstract

The injured skin produces a number of mediators that directly or indirectly modulate cell chemotaxis, migration, proliferation, and angiogenesis. Components of the kinin pathway including the kinin B1 receptor (B1R) have been found to occur in the human skin, but information about its role on keratinocyte biology is still scarce. Our aim was to determine whether stimulation of B1R causes the secretion of IL-4 and/or VEGF from human keratinocytes and to evaluate the role of the B1R agonist Lys-des[Arg9]bradykinin and IL-4 on various stages of angiogenesis, such as cell migration, proliferation, and release of metalloproteases. By using ELISA and Western blotting, we showed that HaCaT keratinocytes stimulated with the B1R agonist release IL-4 and VEGF. Stimulation of B1R also caused transient c-JunN-terminal kinase phosphorylation and JunB nuclear translocation, transcription factor that regulates IL-4 expression. The 3D-angiogenesis assay, performed on spheroids of EA.hy923 endothelial cells embedded in a collagen matrix, showed that their cumulative sprout area increased significantly following stimulation with either IL-4 or B1R agonist. Furthermore, these ligands produced significant endothelial cell migration and release of metalloproteases 2 and 9, but did not increase endothelial cell proliferation as measured by 5-bromo-2′-deoxyuridine incorporation. Our results provide experimental evidence that establishes IL-4 and B1R agonist as important angiogenic factors of relevance for skin repair.

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Acknowledgments

This work was supported by Grants 3130385 (CM) and 1110464 (CDF) from Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT, Chile), a Ph.D. Fellowship 63080006 (AJM) from Consejo Nacional de Ciencia y Tecnologia (CONICYT, Chile), and Grant D-2010-02 (AJM) from Direccion de Investigacion y Desarrollo, Universidad Austral de Chile (Chile). The authors also wish to thank Dr. Jose Sarmiento for his help and technical support with measurements of [Ca2+]i and Prof. Kanti D. Bhoola for the critical reading of the manuscript and helpful suggestions.

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  1. Laboratorio de Patologia Celular, Instituto de Anatomia, Histologia y Patologia, Universidad Austral de Chile, Isla Teja, PO Box 567, Valdivia, Chile

    Astrid J. Mejia, Carola E. Matus, Francisca Pavicic, Miguel Concha, Pamela Ehrenfeld & Carlos D. Figueroa

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  1. Astrid J. Mejia
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  2. Carola E. Matus
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Correspondence to Carlos D. Figueroa.

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Mejia, A.J., Matus, C.E., Pavicic, F. et al. Intracellular signaling pathways involved in the release of IL-4 and VEGF from human keratinocytes by activation of kinin B1 receptor: functional relevance to angiogenesis. Arch Dermatol Res 307, 803–817 (2015). https://doi.org/10.1007/s00403-015-1595-6

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