Abstract
Airflow obstruction in chronic airway disease is associated with airway and pulmonary vascular remodeling, of which the molecular mechanisms are poorly understood. Paracrine actions of angiogenic factors released by resident or infiltrating inflammatory cells following activation by proinflammatory cytokines in diseased airways could play a major role in the airway vascular remodeling process. Here, the proinflammatory cytokines interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were investigated on cell cultures of human airway smooth muscle (ASM) for their effects on mRNA induction and protein release of the angiogenic peptide, vascular endothelial growth factor (VEGF). IL-1β (0.5 ng/mL) and TNF-α (10ng/mL) each increased VEGF mRNA (3.9 and 1.7 kb) expression in human ASM cells, reaching maximal levels between 16 and 24 and 4 and 8h, respectively. Both cytokines also induced a time-dependent release of VEGF, which was not associated with increased ASM growth. Preincubation of cells with 1μM dexamethasone abolished enhanced release of VEGF by TNF-α. The data suggest that human ASM cells express and secrete VEGF in response to proinflammatory cytokines and may participate in paracrine inflammatory mechanisms of vascular remodeling in chronic airway disease.
Similar content being viewed by others
References
Hogg, J. C. (1999) Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 54, 283.
Hoshino, M., Nakamura, Y., and Hamid, Q. A. (2001) Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma. J. Allergy Clin. Immunol. 107, 1034–1038.
McDonald, D. M. (2001) Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am. J. Respir. Crit. Care Med. 164, S39-S45.
Wilson, J. (2000) The bronchial microcirculation in asthma. Clin. Exp. Allergy, 30(Suppl. 1), 51–53.
Kranenburg, A. R., De Boer, W. I., Alagappan, V. K., Sterk, P. J., and Sharma, H. S. (2005) Enhanced bronchial expression of vascular endothelial growth factor and receptors (flk-1 and flt-1) in patients with chronic obstructive pulmonary disease. Thorax, 60, 106–113.
Kranenburg, A. R., De Boer, W. I., Van Krieken, J. H., et al. (2002) Enhanced expression of fibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease. Am. J. Respir. Cell. Mol. Biol. 27, 517–525.
Carroll, N. G., Cooke, C., and James, A. L. (1997) Bronchial blood vessel dimensions in asthma. Am. J. Respir. Crit. Care Med. 155, 689–695.
Wilson, J. W. and Kotsimbos, T. (2003) Airway vascular remodeling in asthma. Curr. Allergy Asthma Rep. 3, 153–158.
Knox, A. J., Corbett, L., Stocks, J., Holland, E., Zhu, Y. M., and Pang, L. (2001) Human airway smooth muscle cells secrete vascular endothelial growth factor: up-regulation by bradykinin via a protein kinase C and prostanoid-dependent mechanism. FASEB J. 15, 2480–2488.
McKay, S. and Sharma, H. S. (2002) Autocrine regulation of asthmatic airway inflammation: role of airway smooth muscle. Respir. Res. 3, 11.
McKay, S., Hirst, S. J., Haas, M. B. et al. (2000) Tumor necrosis factor-alpha enhances mRNA expression and secretion of interleukin-6 in cultured human airway smooth muscle cells. Am. J. Respir. Cell. Mol. Biol. 23, 103–111.
Panettieri, R. A. Jr. (2003) Airway smooth muscle: immunomodulatory cells that modulate airway remodeling? Respir. Physiol. Neurobiol. 137, 277–293.
Barnes, P. J., Chung, K. F., and Page, C. P. (1998) Inflammatory mediators of asthma: an update. Pharmacol. Rev. 50, 515–596.
Tliba, O., Tliba, S., Da Huang, C., et al. (2003) Tumor necrosis factor alpha modulates airway smooth muscle function via the autocrine action of interferon beta. J. Biol. Chem. 278, 50,615–50,623.
Moore, P. E., Lahiri, T., Laporte, J. D., Church, T., Panettieri, R. A., Jr., and Shore, S. A. (2001) Selected contribution: synergism between TNF-alpha and IL-1 beta in airway smooth muscle cells: implications for beta-adrenergic responsiveness. J. Appl. Physiol. 91, 1467–1474.
Carmeliet, P. (2003) Angiogenesis in health and disease. Nat. Med. 9, 653–660.
Tischer, E., Mitchell, R., Hartman, T., et al. (1991) The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266, 11,947–11,954.
Voelkel, N. F., Cool, C., Taraceviene-Stewart, L. et al. (2002) Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Crit. Care Med. 30, S251-S256.
Hoshino, M., Takahashi, M., and Aoike, N. (2001) Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J. Allergy. Clin. Immunol. 107, 295–301.
Reinders, M. E., Sho, M., Izwa, A., et al. (2003) Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J. Clin. Invest. 112, 1655–1665.
McKay, S., de Jongste, J. C., Saxena, P. R., and Sharma, H. S. (1998) Angiotensin II induces hypertrophy of human airway smooth muscle cells: expression of transcription factors and transforming growth factor-beta1. Am. J. Respir. Cell. Mol. Biol. 18, 823–833.
Stewart, A. G., Tomlinson, P. R., Fernandes, D. J., Wilson, J. W., and Harris, T. (1995) Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle. Am. J. Respir. Cell. Mol. Biol. 12, 110–119.
Cucina, A., Borrelli, V., Randone, B., Coluccia, P., Sapienza, P., and Cavallaro, A. (2003) Vascular endothelial growth factor increases the migration and proliferation of smooth muscle cells through the mediation of growth factors released by endothelial cells. J. Surg. Res. 109, 16–23.
Kazi, A. S., Lotfi, S., Goncharova, E. A., et al. (2004) Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L539-L545.
Wu, Y., Zhang, Q., Ann, D. K., et al. (2004) Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts. Am. J. Physiol. Cell. Physiol. 286, C905-C912.
Kim, I., Moon, S. O., Kim, S. H., Kim, H. J., Koh, Y. S., and Koh, G. Y. (2001) Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J. Biol. Chem. 276, 7614–7620.
Richter, A., Puddicombe, S. M., Lordan, J. L., et al. (2001) The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am. J. Respir. Cell. Mol. Biol. 25, 385–391.
Wen, F. Q., Liu, X., Manda, W., et al. (2003) TH2 Cytokine-enhanced and TGF-beta-enhanced vascular endothelial growth factor production by cultured human airway smooth muscle cells is attenuated by IFN-gamma and corticosteroids. J. Allergy Clin. Immunol. 111, 1307–1318.
Inai, T., Mancuso, M., Hashizume, H., et al. (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels and appearance of basement membrane ghosts. Am. J. Pathol. 165, 35–52.
Lee, Y. C., Kwak, Y. G., and Song, C. H. (2002) Contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma. J. Immunol. 168, 3595–3600.
Kanazawa, H., Asai, K., Hirata, K., and Yoshikawa, J. (2003) Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Am. J. Med. 114, 354–358.
Kasahara, Y., Tuder, R. M., Cool, C. D., Lynch, D. A., Flores, S. C., and Voelkel, N. F. (2001) Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am. J. Respir. Crit. Care Med. 163, 737–744.
Chetta, A., Zanini, A., Foresi, A., et al. (2003) Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone. Am. J. Respir. Crit. Care Med. 167, 751–757.
Hoshino, M., Takahashi, M., Takai, Y., Sim, J., and Aoike, N. (2001) Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma. Clin. Exp. Allergy. 31, 722–730.
Rees, D. A., Lewis, B. M., Lewis, M. D., Francis, K., Scanlon, M. F., and Ham, J. (2003) Adenosine-induced IL-6 expression in pituitary folliculostellate cells is mediated via A2b adenosine receptors coupled to PKC and p38 MAPK. Br. J. Pharmacol. 140, 764–772.
Ammit, A. J., Lazaar, A. L., Irani, C., et al. (2002) Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by glucocorticoids and beta-agonists. Am. J. Respir. Cell Mol. Biol. 26, 465–474.
Fehrenbach, H., Kasper, M., Haase, M., Schuh, D., and Muller, M. (1999) Differential immunolocalization of VEGF in rat and human adult lung, and in experiment rat lung fibrosis: light, fluorescence, and electron microscopy. Anat. Rec. 254, 61–73.
Shehata, S. M., Mooi, W. J., Okazaki, T., El-Banna, I., Sharma, H. S., and Tibboel, D. (1999) Enhanced expression of vascular endothelial growth factor in lungs of newborn infants with congenital diaphragmatic hernia and pulmonary hypertension. Thorax 54, 427–431.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Alagappan, V.K.T., McKay, S., Widyastuti, A. et al. Proinflammatory cytokines upregulate mRNA expression and secretion of vascular endothelial growth factor in cultured human airway smooth muscle cells. Cell Biochem Biophys 43, 119–129 (2005). https://doi.org/10.1385/CBB:43:1:119
Issue Date:
DOI: https://doi.org/10.1385/CBB:43:1:119