title: IL-1alpha induces angiogenesis in brain endothelial cells in vitro: implications for brain angiogenesis after acute injury.
abstract: Inflammation is a major contributor to neuronal injury and is associated with poor outcome after acute brain injury such as stroke. The pro-inflammatory cytokine interleukin (IL)-1 is a critical regulator of cerebrovascular inflammation after ischemic injury, mainly through action of both of its isoforms, IL-1α and IL-1β, at the brain endothelium. In contrast, the differential action of these ligands on endothelial activation and post-stroke angiogenesis is largely unknown. Here, we demonstrate that IL-1α is chronically elevated in the brain after experimental stroke suggesting that it is present during post-stroke angiogenic periods. Furthermore, we demonstrate that IL-1α is a potent mediator of endothelial activation and inducer of angiogenic markers in endothelial cells in vitro. Using brain endothelial cell lines, we found that IL-1α was significantly more potent than IL-1β at inducing endothelial cell activation, as measured by expression of the pro-angiogenic chemokine CXCL-1. IL-1α also induced strong expression of the angiogenic mediator IL-6 in a concentration-dependent manner. Furthermore, IL-1α induced significant proliferation and migration of endothelial cells, and promoted formation of tube-like structures that are established key hallmarks of angiogenesis in vitro. Finally, all of those responses were blocked by the IL-1 receptor antagonist (IL-1RA). In conclusion, our data highlights a potential new role for IL-1 in brain repair mechanisms and identifies IL-1α as a potential new therapy to promote post-stroke angiogenesis. Inflammation is a major contributor to neuronal injury and is associated with poor outcome after neurotrauma. We demonstrate that cytokine IL-1α is chronically elevated in the brain after experimental stroke suggesting that it is present chronically post-stroke. We demonstrate that IL-1α is a potent mediator of endothelial activation and inducer of angiogenic markers in endothelial cells. Our data highlights a new role for IL-1 in brain repair mechanisms and identifies IL-1α as a potential therapy to promote post-stroke angiogenesis.
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Salmeron
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Takuma
authors.initials: T
authors.lastname: Aihara
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Redondo-Castro
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinteaux
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Bix
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications* / Q000209:etiology; D002340:Carotid Artery Diseases / Q000150:complications / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D007839:Functional Laterality; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism; D053582:Interleukin-1alpha / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000209:etiology*; D013997:Time Factors
chemical_list: D016207:Cytokines; D053582:Interleukin-1alpha; D053583:Interleukin-1beta
keywords: angiogenesis; cerebral ischemia; endothelia; inflammation; interleukin-1