title: IL-17 contributes to angiogenesis in rheumatoid arthritis.
abstract: Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis. Local expression of IL-17 in mouse ankles increases vascularity. We further demonstrate that IL-17 is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Additionally, IL-17, in concentrations present in the RA joint, induces human lung microvascular endothelial cell (HMVEC) migration mediated through the PI3K/AKT1 pathway. Furthermore, suppression of the PI3K pathway markedly reduces IL-17-induced tube formation. We also show that both IL-17-induced HMVEC chemotaxis and tube formation are mediated primarily through IL-17 receptor C. Neutralization of either IL-17 in RA synovial fluids or IL-17 receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid. Finally, RA synovial fluid immunoneutralized with anti-IL-17 and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone. These observations identify a novel function for IL-17 as an angiogenic mediator in RA, supporting IL-17 as a therapeutic target in RA.
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Pickens
authors.forename: Michael V
authors.initials: MV
authors.lastname: Volin
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mandelin
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
mesh_terms: D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D000843:Ankle Joint / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D002464:Cell Migration Inhibition / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053722:Receptors, Interleukin-17 / Q000502:physiology; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D042501:Angiogenic Proteins; C109985:IL17RA protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D042461:Vascular Endothelial Growth Factor A