title: Interleukin-19 increases angiogenesis in ischemic hind limbs by direct effects on both endothelial cells and macrophage polarization.
abstract: Hypoxia in ischemic limbs typically initiates angiogenic and inflammatory factors to promote angiogenesis in attempt to restore perfusion. There is a gap in our knowledge concerning the role of anti-inflammatory interleukins in angiogenesis, macrophage polarization, and endothelial cell activation. Interleukin-19 is a unique anti-inflammatory Th2 cytokine that promotes angiogenic effects in cultured endothelial cells (EC); the purpose of this study was to characterize a role for IL-19 in restoration of blood flow in hind-limb ischemia, and define potential mechanisms. Hind limb ischemia was induced by femoral artery ligation, and perfusion quantitated using Laser Doppler Perfusion Imaging (LDPI). Wild type mice which received i.p. injections of rIL-19 (10ng/g/day) showed significantly increased levels of perfusion compared to PBS controls. LDPI values were significantly decreased in IL-19(-/-) mice when compared to wild type mice. IL-19(-/-) mice injected with rIL-19 had significantly increased LDPI compared with PBS control mice. Significantly increased capillary density was quantitated in rIL-19 treated mice, and significantly less capillary density in IL-19(-/-) mice. Multiple cell types participate in IL-19 induced angiogenesis. IL-19 treatment of human microvascular EC induced expression of angiogenic cytokines. M2 macrophage marker and VEGF-A expression were significantly increased in macrophage and the spleen from rIL-19 injected mice, and M1 marker expression was significantly increased in the spleen from IL-19(-/-) compared with controls. Plasma VEGF-A levels are higher in rIL-19 injected mice. IL-19 decreased the expression of anti-angiogenic IL-12 in the spleen and macrophage. This study is the first to implicate IL-19 as a novel pro-angiogenic interleukin and suggests therapeutic potential for this cytokine.
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: James
authors.initials: J
authors.lastname: Richards
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gabunia
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Sheri E
authors.initials: SE
authors.lastname: Kelemen
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Farah
authors.initials: F
authors.lastname: Kako
authors.affiliation: Department of Surgery, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: mautieri@temple.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Autieri
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D016764:Cell Polarity; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D007378:Interleukins; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics; D010641:Phenotype; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C498891:Il19 protein, mouse; D053762:Interleukin-12 Subunit p40; D007378:Interleukins; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10
keywords: Angiogenesis; Endothelial cell; Hind limb ischemia; Interleukin-19; Macrophage polarization