title: Interleukin-19 induces angiogenesis in the absence of hypoxia by direct and indirect immune mechanisms.
abstract: Neovascularization and inflammation are independent biological processes but are linked in response to injury. The role of inflammation-dampening cytokines in the regulation of angiogenesis remains to be clarified. The purpose of this work was to test the hypothesis that IL-19 can induce angiogenesis in the absence of tissue hypoxia and to identify potential mechanisms. Using the aortic ring model of angiogenesis, we found significantly reduced sprouting capacity in aortic rings from IL-19(-/-) compared with wild-type mice. Using an in vivo assay, we found that IL-19(-/-) mice respond to vascular endothelial growth factor (VEGF) significantly less than wild-type mice and demonstrate decreased capillary formation in Matrigel plugs. IL-19 signals through the IL-20 receptor complex, and IL-19 induces IL-20 receptor subunit expression in aortic rings and cultured human vascular smooth muscle cells, but not endothelial cells, in a peroxisome proliferator-activated receptor-γ-dependent mechanism. IL-19 activates STAT3, and IL-19 angiogenic activity in aortic rings is STAT3-dependent. Using a quantitative RT-PCR screening assay, we determined that IL-19 has direct proangiogenic effects on aortic rings by inducing angiogenic gene expression. M2 macrophages participate in angiogenesis, and IL-19 has indirect angiogenic effects, as IL-19-stimulated bone marrow-derived macrophages secrete proangiogenic factors that induce greater sprouting of aortic rings than unstimulated controls. Using a quantitative RT-PCR screen, we determined that IL-19 induces expression of angiogenic cytokines in bone marrow-derived macrophages. Together, these data suggest that IL-19 can promote angiogenesis in the absence of hypoxia by at least two distinct mechanisms: 1) direct effects on vascular cells and 2) indirect effects by stimulation of macrophages.
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Farah
authors.initials: F
authors.lastname: Kako
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
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, Pennsylvania.
authors.forename: Mitali
authors.initials: M
authors.lastname: Ray
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
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, Pennsylvania.
authors.forename: Ross N
authors.initials: RN
authors.lastname: England
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Bashar
authors.initials: B
authors.lastname: Kako
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Rosario G
authors.initials: RG
authors.lastname: Scalia
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania mautieri@temple.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Autieri
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005838:Genotype; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins; D007797:Laminin / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011509:Proteoglycans / Q000494:pharmacology; D034622:RNA Interference; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D004338:Drug Combinations; C498891:Il19 protein, mouse; D007378:Interleukins; D007797:Laminin; D047495:PPAR gamma; D011509:Proteoglycans; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C492510:interleukin-20 receptor; C059485:matrigel; D016753:Interleukin-10; D003094:Collagen
keywords: angiogenesis; cytokines; endothelial cell; macrophage; vascular smooth muscle