title: IL-32 promotes angiogenesis.
abstract: IL-32 is a multifaceted cytokine with a role in infections, autoimmune diseases, and cancer, and it exerts diverse functions, including aggravation of inflammation and inhibition of virus propagation. We previously identified IL-32 as a critical regulator of endothelial cell (EC) functions, and we now reveal that IL-32 also possesses angiogenic properties. The hyperproliferative ECs of human pulmonary arterial hypertension and glioblastoma multiforme exhibited a markedly increased abundance of IL-32, and, significantly, the cytokine colocalized with integrin αVβ3. Vascular endothelial growth factor (VEGF) receptor blockade, which resulted in EC hyperproliferation, increased IL-32 three-fold. Small interfering RNA-mediated silencing of IL-32 negated the 58% proliferation of ECs that occurred within 24 h in scrambled-transfected controls. Reduction of IL-32 neither affected apoptosis (insignificant changes in Bak-1, Bcl-2, Bcl-xL, lactate dehydrogenase, annexin V, and propidium iodide) nor VEGF or TGF-β levels, but siIL-32-transfected adult and neonatal ECs produced up to 61% less NO, IL-8, and matrix metalloproteinase-9, and up to 3-fold more activin A and endostatin. In coculture-based angiogenesis assays, IL-32γ dose-dependently increased tube formation up to 3-fold; an αVβ3 inhibitor prevented this activity and reduced IL-32γ-induced IL-8 by 85%. In matrigel plugs loaded with IL-32γ, VEGF, or vehicle and injected into live mice, we observed the anticipated VEGF-induced increase in neocapillarization (8-fold versus vehicle), but unexpectedly, IL-32γ was equally angiogenic. A second signal such as IFN-γ was required to render cells responsive to exogenous IL-32γ; importantly, this was confirmed using a completely synthetic preparation of IL-32γ. In summary, we add angiogenic properties that are mediated by integrin αVβ3 but VEGF-independent to the portfolio of IL-32, implicating a role for this versatile cytokine in pulmonary arterial hypertension and neoplastic diseases.
authors: Ritchie Centre, Monash Institute of Medical Research, Monash University, Melbourne, Victoria 3168, Australia;
authors: Claudia A
authors: CA
authors: Nold-Petry
authors: Ina
authors: I
authors: Rudloff
authors: Yvonne
authors: Y
authors: Baumer
authors: Menotti
authors: M
authors: Ruvo
authors: Daniela
authors: D
authors: Marasco
authors: Paolo
authors: P
authors: Botti
authors: Laszlo
authors: L
authors: Farkas
authors: Steven X
authors: SX
authors: Cho
authors: Jarod A
authors: JA
authors: Zepp
authors: Tania
authors: T
authors: Azam
authors: Hannah
authors: H
authors: Dinkel
authors: Brent E
authors: BE
authors: Palmer
authors: William A
authors: WA
authors: Boisvert
authors: Carlyne D
authors: CD
authors: Cool
authors: Laima
authors: L
authors: Taraseviciene-Stewart
authors: Bas
authors: B
authors: Heinhuis
authors: Leo A B
authors: LA
authors: Joosten
authors: Charles A
authors: CA
authors: Dinarello
authors: Norbert F
authors: NF
authors: Voelkel
authors: Marcel F
authors: MF
authors: Nold
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D043169:Endostatins / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D005909:Glioblastoma / Q000196:embryology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D009589:Nitrogen Oxides / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043169:Endostatins; C496971:IL32 protein, human; D039302:Integrin alphaVbeta3; D016209:Interleukin-8; D007378:Interleukins; D009589:Nitrogen Oxides; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C422405:activin A; D028341:Activins; D007371:Interferon-gamma; D040262:Receptors, Vascular Endothelial Growth Factor; D020780:Matrix Metalloproteinase 9