Ritchie Centre, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, VIC 3168, Australia
Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, United States
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerce, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, 80134 Naples, Italy
Department of Pharmacy, University of Naples Federico II, 80134 Naples, Italy
ArisGen SA, 1228 Plan-les-Ouates, Switzerland
Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States
Department of Medicine, University of Colorado Denver, Aurora, CO 80045, United States
Department of Pathology, University of Colorado Denver, Aurora, CO 80045, United States
Radboud University Medical Center, 6500 HB Nijmegen, Netherlands
Pulmonary and Critical Care Medicine Division, Molecular Medicine Research Building, Virginia Commonwealth University, Broad Street, Richmond, VA 23298, United States
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Zepp, J. A., Nold-Petry, C. A., Dinarello, C. A., Nold, M. F., Protection from RNA and DNA viruses by IL-32 (2011) J. Immunol., 186, pp. 4110-4118
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Lee, S., Kim, J. H., Kim, H., Kang, J. W., Kim, S. H., Yang, Y., Kim, J., Yoon, D. Y., Activation of the interleukin-32 proinflammatory pathway in response to human papillomavirus infection and overexpression of interleukin-32 controls the expression of the human papillomavirus oncogene (2011) Immunology, 132, pp. 410-420
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Tuder, R. M., Voelkel, N. F., Pulmonary hypertension and inflammation (1998) Journal of Laboratory and Clinical Medicine, 132 (1), pp. 16-24
Voelkel, N. F., Gomez-Arroyo, J. G., Abbate, A., Bogaard, H. J., Nicolls, M. R., Pathobiology of pulmonary arterial hypertension and right ventricular failure (2012) Eur. Respir. J., 40, pp. 1555-1565
Tuder, R. M., Chacon, M., Alger, L., Wang, J., Taraseviciene-Stewart, L., Kasahara, Y., Cool, C. D., Semenza, G. L., Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: Evidence for a process of disordered angiogenesis (2001) J. Pathol., 195, pp. 367-374
Hackeng, T. M., Fernandez, J. A., Dawson, P. E., Kent, S. B. H., Griffin, J. H., Chemical synthesis and spontaneous folding of a multidomain protein: Anticoagulant microprotein S (2000) Proceedings of the National Academy of Sciences of the United States of America, 97 (26), pp. 14074-14078. , DOI 10. 1073/pnas. 260239797
Wang, W., Wang, Y. L., Chen, X. Y., Li, Y. T., Hao, W., Jin, Y. P., Han, B., Dexamethasone attenuates development of monocrotaline-induced pulmonary arterial hypertension (2011) Mol. Biol. Rep., 38, pp. 3277-3284
Wort, S. J., Ito, M., Chou, P. C., Mc Master, S. K., Badiger, R., Jazrawi, E., De Souza, P., Pinhu, L., Synergistic induction of endothelin-1 by tumor necrosis factor alpha and interferon is due to enhanced NF-kappaB binding and histone acetylation at specific kB sites (2009) J. Biol. Chem., 284, pp. 24297-24305
Lee, M. -S., Sarvetnick, N., Induction of vascular addressins and adhesion molecules in the pancreas of IFN- transgenic mice (1994) Journal of Immunology, 152 (9), pp. 4597-4603
Westphal, J. R., Willems, H. W., Tax, W. J. M., Koene, R. A. P., Ruiter, D. J., De Waal, R. M. W., The proliferative response of human T cells to allogeneic IFN-gamma-treated endothelial cells is mediated via both CD2/LFA-3 and LFA-1/ICAM-1 and -2 adhesion pathways (1993) Transplant Immunology, 1 (3), pp. 183-191
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Waugh, D. J., Wilson, C., The interleukin-8 pathway in cancer (2008) Clin. Cancer Res., 14, pp. 6735-6741
Rai, P. R., Cool, C. D., King, J. A., Stevens, T., Burns, N., Winn, R. A., Kasper, M., Voelkel, N. F., The cancer paradigm of severe pulmonary arterial hypertension (2008) Am. J. Respir. Crit. Care Med., 178, pp. 558-564
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Cho, K. A., Jun, Y. H., Suh, J. W., Kang, J. S., Choi, H. J., Woo, S. Y., Orientia tsutsugamushi induced endothelial cell activation via the NOD1-IL-32 pathway (2010) Microb. Pathog., 49, pp. 95-104
IL-32 Promotes Angiogenesis
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 alpha v beta(3). 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-x(L), lactate dehydrogenase, annexin V, and propidium iodide) nor VEGF or TGF-beta 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-32 gamma dose-dependently increased tube formation up to 3-fold; an alpha v beta(3) inhibitor prevented this activity and reduced IL-32 gamma-induced IL-8 by 85%. In matrigel plugs loaded with IL-32 gamma, VEGF, or vehicle and injected into live mice, we observed the anticipated VEGF-induced increase in neocapillarization (8-fold versus vehicle), but unexpectedly, IL-32 gamma was equally angiogenic. A second signal such as IFN-gamma was required to render cells responsive to exogenous IL-32 gamma; importantly, this was confirmed using a completely synthetic preparation of IL-32 gamma. In summary, we add angiogenic properties that are mediated by integrin alpha v beta(3) but VEGF-independent to the portfolio of IL-32, implicating a role for this versatile cytokine in pulmonary arterial hypertension and neoplastic diseases.