Abstract
Interleukin (IL)-13 is a cytokine produced by type 2 helper T cells that has pathophysiological roles in allergic inflammation and fibrosis formation. IL-13 shares many functional properties with IL-4, which promotes apoptosis of endothelial cells (ECs). We here investigated the effects of IL-13 on apoptosis using human coronary artery endothelial cells (HCAECs). Assessment by WST-1 assay demonstrated that IL-13 as well as IL-4 significantly inhibited cell growth. IL-13 significantly attenuated the cell viability and induced apoptosis of HCAECs as well. Expression of mRNA for vascular endothelial cell growth factor, which maintains survival of ECs, was significantly diminished by IL-13. The effects of IL-13 and IL-4 were abolished by depletion of STAT6 using RNA interference. These results suggest that IL-13 attenuates EC viability by inducing apoptosis, and that STAT6 plays pivotal roles on IL-13− and IL-4–induced apoptosis in ECs.
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Hershey GK : IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol 2003; 111: 677–691.
Kotowicz K, Callard RE, Friedrich K, Matthews DJ, Klein N : Biological activity of IL-4 and IL-13 on human endothelial cells: functional evidence that both cytokines act through the same receptor. Int Immunol 1996; 8: 1915–1925.
Shimoda K, Deursen J, Sangster MY, et al: Lack of IL-4–induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996; 380: 630–633.
Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S : Impaired IL-13–mediated functions of macrophages in STAT6-deficient mice. J Immunol 1996; 157: 3220–3222.
Palmer-Crocker RL, Hughes CC, Pober JS : IL-4 and IL-13 activate the JAK2 tyrosine kinase and Stat6 in cultured human vascular endothelial cells through a common pathway that does not involve the γc chain. J Clin Invest 1996; 98: 604–609.
Gooch JL, Christy B, Yee D : STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. Neoplasia 2002; 4: 324–331.
Obiri NI, Hillman GG, Haas GP, Sud S, Puri RK : Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. J Clin Invest 1993; 91: 88–93.
Toi M, Bicknell R, Harris AL : Inhibition of colon and breast carcinoma cell growth by interleukin-4. Cancer Res 1992; 52: 275–279.
Topp MS, Papadimitriou CA, Eitelbach F, et al: Recombinant human interleukin 4 has antiproliferative activity on human tumor cell lines derived from epithelial and nonepithelial histologies. Cancer Res 1995; 55: 2173–2176.
Aoudjehane L, Podevin P, Scatton O, et al: Interleukin-4 induces human hepatocyte apoptosis through a Fas-independent pathway. FASEB J 2007; 21: 1433–1444.
Kim J, Cheon IS, Won YJ, Na HJ, Kim YM, Choe J : IL-4 inhibits cell cycle progression of human umbilical vein endothelial cells by affecting p53, p21(Waf1), cyclin D1, and cyclin E expression. Mol Cells 2003; 16: 92–96.
Lee YW, Kuhn H, Hennig B, Toborek M : IL-4 induces apoptosis of endothelial cells through the caspase-3–dependent pathway. FEBS Lett 2000; 485: 122–126.
Volpert OV, Fong T, Koch AE, et al: Inhibition of angiogenesis by interleukin 4. J Exp Med 1998; 188: 1039–1046.
Mascareno E, El-Shafei M, Maulik N, et al: JAK/STAT signaling is associated with cardiac dysfunction during ischemia and reperfusion. Circulation 2001; 104: 325–329.
Nishimura Y, Inoue T, Nitto T, Morooka T, Node K : Increased interleukine-13 levels in patients with chronic heart failure. Int J Cardiol 2008 ( in press).
Foteinos G, Afzal AR, Mandal K, Jahangiri M, Xu Q : Anti-heat shock protein 60 autoantibodies induce atherosclerosis in apolipoprotein E–deficient mice via endothelial damage. Circulation 2005; 112: 1206–1213.
Mosmann T : Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.
Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J : Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 2007; 49: 1015–1026.
Liu Y, Cox SR, Morita T, Kourembanas S : Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 1995; 77: 638–643.
Seghezzi G, Patel S, Ren CJ, et al: Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 1998; 141: 1659–1673.
Nishimura Y, Nitto T, Inoue T, Node K : IL-13 attenuates vascular tube formation via JAK2-STAT6 pathway. Circ J 2008; 72: 469–475.
Evans PC, Kilshaw PJ : Interleukin-13 protects endothelial cells from apoptosis and activation: association with the protective genes A20 and A1. Transplantation 2000; 70: 928–934.
Grehan JF, Levay-Young BK, Fogelson JL, Francois-Bongarcon V, Benson BA, Dalmasso AP : IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway: J Immunol 2005; 175: 1903–1910.
Haas CS, Amin MA, Allen BB, et al: Inhibition of angiogenesis by interleukin-4 gene therapy in rat adjuvant-induced arthritis. Arthritis Rheum 2006; 54: 2402–2414.
Bennett BL, Cruz R, Lacson RG, Manning AM : Interleukin-4 suppression of tumor necrosis factor α−stimulated E-selectin gene transcription is mediated by STAT6 antagonism of NF-κB. J Biol Chem 1997; 272: 10212–10219.
Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM : NF-κB mediates αvβ3 integrin–induced endothelial cell survival. J Cell Biol 1998; 141: 1083–1093.
Grosjean J, Kiriakidis S, Reilly K, Feldmann M, Paleolog E : Vascular endothelial growth factor signaling in endothelial cell survival: a role for NFκB. Biochem Biophys Res Commun 2006; 340: 984–994.
Daniel S, Arvelo MB, Patel VI, et al: A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood 2004; 104: 2376–2384.
Longo CR, Arvelo MB, Patel VI, et al: A20 protects from CD40-CD40 ligand–mediated endothelial cell activation and apoptosis. Circulation 2003; 108: 1113–1118.
Kaplan MH, Daniel C, Schindler U, Grusby MJ : Stat proteins control lymphocyte proliferation by regulating p27Kip1 expression. Mol Cell Biol 1998; 18: 1996–2003.
Bouton LA, Ramirez CD, Bailey DP, et al: Costimulation with interleukin-4 and interleukin-10 induces mast cell apoptosis and cell cycle arrest: p53 and the mitochondrion. Exp Hematol 2004; 32: 1137–1145.
Bailey DP, Kashyap M, Mirmonsef P, et al: Interleukin-4 elicits apoptosis of developing mast cells via a Stat6-dependent mitochondrial pathway. Exp Hematol 2004; 32: 52–59.
Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E : Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1: 1024–1028.
Saleh M, Davis ID, Wilks AF : The paracrine role of tumour-derived mIL-4 on tumour-associated endothelium. Int J Cancer 1997; 72: 664–672.
Griga T, Hebler U, Voigt E, Tromm A, May B : Interleukin-4 inhibits the increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease. Hepatogastroenterology 2000; 47: 1604–1607.
Matsumoto K, Ohi H, Kanmatsuse K : Interleukin-4 cooperates with interleukin-10 to inhibit vascular permeability factor release by peripheral blood mononuclear cells from patients with minimal-change nephrotic syndrome. Am J Nephrol 1999; 19: 21–27.
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Nishimura, Y., Nitto, T., Inoue, T. et al. STAT6 Mediates Apoptosis of Human Coronary Arterial Endothelial Cells by Interleukin-13. Hypertens Res 31, 535–541 (2008). https://doi.org/10.1291/hypres.31.535
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DOI: https://doi.org/10.1291/hypres.31.535
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