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: Claudia A Nold-Petry, Ina Rudloff, Yvonne Baumer, Menotti Ruvo, Daniela Marasco, Paolo Botti, Laszlo Farkas, Steven X Cho, Jarod A Zepp, Tania Azam, Hannah Dinkel, Brent E Palmer, William A Boisvert, Carlyne D Cool, Laima Taraseviciene-Stewart, Bas Heinhuis, Leo A B Joosten, Charles A Dinarello, Norbert F Voelkel, Marcel F Nold
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 2 Pg. 589-602 (Jan 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24337385 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endostatins
• IL32 protein, human
• Integrin alphaVbeta3
• Interleukin-8
• Interleukins
• Nitrogen Oxides
• Transforming Growth Factor beta1
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• activin A
• Activins
• Interferon-gamma
• Receptors, Vascular Endothelial Growth Factor
• Matrix Metalloproteinase 9

Topics

• Activins (metabolism)
• Animals
• Apoptosis (physiology)
• Cells, Cultured
• Endostatins (metabolism)
• Familial Primary Pulmonary Hypertension
• Glioblastoma (embryology, pathology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypertension, Pulmonary (metabolism, pathology)
• Integrin alphaVbeta3 (metabolism)
• Interferon-gamma (metabolism)
• Interleukin-8 (metabolism)
• Interleukins (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Neovascularization, Pathologic (metabolism, pathology)
• Nitrogen Oxides (metabolism)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)