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. 1997 Apr 1;99(7):1767–1773. doi: 10.1172/JCI119341

Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids.

C M Lilly 1, H Nakamura 1, H Kesselman 1, C Nagler-Anderson 1, K Asano 1, E A Garcia-Zepeda 1, M E Rothenberg 1, J M Drazen 1, A D Luster 1
PMCID: PMC507998  PMID: 9120022

Abstract

Eotaxin is a potent and specific eosinophil chemoattractant that is mobilized in the respiratory epithelium after allergic stimulation. Pulmonary levels of eotaxin mRNA are known to increase after allergen exposure in sensitized animals. In this study we demonstrate that TNF alpha and IL-1beta induce the accumulation of eotaxin mRNA in the pulmonary epithelial cell lines A549 and BEAS 2B in a dose-dependent manner. Cytokine-induced A549 cell mRNA accumulation was maximal at 4 h and was significantly enhanced when the cells were costimulated with IFNgamma. TNFalpha- and IL-1beta-induced increases in eotaxin mRNA were diminished in a dose-dependent manner by the glucocorticoid dexamethasone and were augmented by the protein synthesis inhibitor cycloheximide. Cytokine-induced increases in eotaxin mRNA expression correlated with increased eotaxin protein production and secretion, and dexamethasone inhibition of cytokine-induced eotaxin mRNA augmentation was associated with diminished eotaxin protein secretion. These findings, together with the known kinetics of TNF alpha and IL-1beta mobilization in asthmatic airways and the potent eosinophil chemotactic effects of eotaxin, define a mechanism linking inflammatory cytokine mobilization to eosinophil recruitment that may be relevant to the pathogenesis of asthma.

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Selected References

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  1. Adelroth E., Rosenhall L., Johansson S. A., Linden M., Venge P. Inflammatory cells and eosinophilic activity in asthmatics investigated by bronchoalveolar lavage. The effects of antiasthmatic treatment with budesonide or terbutaline. Am Rev Respir Dis. 1990 Jul;142(1):91–99. doi: 10.1164/ajrccm/142.1.91. [DOI] [PubMed] [Google Scholar]
  2. Beasley R., Roche W. R., Roberts J. A., Holgate S. T. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis. 1989 Mar;139(3):806–817. doi: 10.1164/ajrccm/139.3.806. [DOI] [PubMed] [Google Scholar]
  3. Borish L., Mascali J. J., Dishuck J., Beam W. R., Martin R. J., Rosenwasser L. J. Detection of alveolar macrophage-derived IL-1 beta in asthma. Inhibition with corticosteroids. J Immunol. 1992 Nov 1;149(9):3078–3082. [PubMed] [Google Scholar]
  4. Bousquet J., Chanez P., Lacoste J. Y., Barnéon G., Ghavanian N., Enander I., Venge P., Ahlstedt S., Simony-Lafontaine J., Godard P. Eosinophilic inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033–1039. doi: 10.1056/NEJM199010113231505. [DOI] [PubMed] [Google Scholar]
  5. Burke C., Power C. K., Norris A., Condez A., Schmekel B., Poulter L. W. Lung function and immunopathological changes after inhaled corticosteroid therapy in asthma. Eur Respir J. 1992 Jan;5(1):73–79. [PubMed] [Google Scholar]
  6. Caput D., Beutler B., Hartog K., Thayer R., Brown-Shimer S., Cerami A. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1670–1674. doi: 10.1073/pnas.83.6.1670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Churchill L., Chilton F. H., Resau J. H., Bascom R., Hubbard W. C., Proud D. Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells. Am Rev Respir Dis. 1989 Aug;140(2):449–459. doi: 10.1164/ajrccm/140.2.449. [DOI] [PubMed] [Google Scholar]
  8. Churchill L., Friedman B., Schleimer R. P., Proud D. Production of granulocyte-macrophage colony-stimulating factor by cultured human tracheal epithelial cells. Immunology. 1992 Jan;75(1):189–195. [PMC free article] [PubMed] [Google Scholar]
  9. DUNNILL M. S. The pathology of asthma, with special reference to changes in the bronchial mucosa. J Clin Pathol. 1960 Jan;13:27–33. doi: 10.1136/jcp.13.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Djukanović R., Wilson J. W., Britten K. M., Wilson S. J., Walls A. F., Roche W. R., Howarth P. H., Holgate S. T. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992 Mar;145(3):669–674. doi: 10.1164/ajrccm/145.3.669. [DOI] [PubMed] [Google Scholar]
  11. Foster P. S., Hogan S. P., Ramsay A. J., Matthaei K. I., Young I. G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996 Jan 1;183(1):195–201. doi: 10.1084/jem.183.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ganzalo J. A., Jia G. Q., Aguirre V., Friend D., Coyle A. J., Jenkins N. A., Lin G. S., Katz H., Lichtman A., Copeland N. Mouse Eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response. Immunity. 1996 Jan;4(1):1–14. doi: 10.1016/s1074-7613(00)80293-9. [DOI] [PubMed] [Google Scholar]
  13. Garcia-Zepeda E. A., Rothenberg M. E., Ownbey R. T., Celestin J., Leder P., Luster A. D. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med. 1996 Apr;2(4):449–456. doi: 10.1038/nm0496-449. [DOI] [PubMed] [Google Scholar]
  14. Griffiths-Johnson D. A., Collins P. D., Rossi A. G., Jose P. J., Williams T. J. The chemokine, eotaxin, activates guinea-pig eosinophils in vitro and causes their accumulation into the lung in vivo. Biochem Biophys Res Commun. 1993 Dec 30;197(3):1167–1172. doi: 10.1006/bbrc.1993.2599. [DOI] [PubMed] [Google Scholar]
  15. Guyre P. M., Girard M. T., Morganelli P. M., Manganiello P. D. Glucocorticoid effects on the production and actions of immune cytokines. J Steroid Biochem. 1988;30(1-6):89–93. doi: 10.1016/0022-4731(88)90080-5. [DOI] [PubMed] [Google Scholar]
  16. Holtzman M. J., Ferdman B., Bohrer A., Turk J. Synthesis of the 1-O-hexadecyl molecular species of platelet-activating factor by airway epithelial and vascular endothelial cells. Biochem Biophys Res Commun. 1991 May 31;177(1):357–364. doi: 10.1016/0006-291x(91)91991-k. [DOI] [PubMed] [Google Scholar]
  17. Jose P. J., Griffiths-Johnson D. A., Collins P. D., Walsh D. T., Moqbel R., Totty N. F., Truong O., Hsuan J. J., Williams T. J. Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med. 1994 Mar 1;179(3):881–887. doi: 10.1084/jem.179.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kay A. B. Asthma and inflammation. J Allergy Clin Immunol. 1991 May;87(5):893–910. doi: 10.1016/0091-6749(91)90408-g. [DOI] [PubMed] [Google Scholar]
  19. Kraft M., Djukanovic R., Torvik J., Cunningham L., Henson J., Wilson S., Holgate S. T., Hyde D., Martin R. Evaluation of airway inflammation by endobronchial and transbronchial biopsy in nocturnal and nonnocturnal asthma. Chest. 1995 Mar;107(3 Suppl):162S–162S. doi: 10.1378/chest.107.3_supplement.162s. [DOI] [PubMed] [Google Scholar]
  20. Kruys V., Marinx O., Shaw G., Deschamps J., Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989 Aug 25;245(4920):852–855. doi: 10.1126/science.2672333. [DOI] [PubMed] [Google Scholar]
  21. Kwon O. J., Au B. T., Collins P. D., Baraniuk J. N., Adcock I. M., Chung K. F., Barnes P. J. Inhibition of interleukin-8 expression by dexamethasone in human cultured airway epithelial cells. Immunology. 1994 Mar;81(3):389–394. [PMC free article] [PubMed] [Google Scholar]
  22. Kwon O. J., Jose P. J., Robbins R. A., Schall T. J., Williams T. J., Barnes P. J. Glucocorticoid inhibition of RANTES expression in human lung epithelial cells. Am J Respir Cell Mol Biol. 1995 May;12(5):488–496. doi: 10.1165/ajrcmb.12.5.7537968. [DOI] [PubMed] [Google Scholar]
  23. Laitinen L. A., Heino M., Laitinen A., Kava T., Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis. 1985 Apr;131(4):599–606. doi: 10.1164/arrd.1985.131.4.599. [DOI] [PubMed] [Google Scholar]
  24. Laitinen L. A., Laitinen A., Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol. 1992 Jul;90(1):32–42. doi: 10.1016/s0091-6749(06)80008-4. [DOI] [PubMed] [Google Scholar]
  25. Marini M., Vittori E., Hollemborg J., Mattoli S. Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J Allergy Clin Immunol. 1992 May;89(5):1001–1009. doi: 10.1016/0091-6749(92)90223-o. [DOI] [PubMed] [Google Scholar]
  26. Mauser P. J., Pitman A. M., Fernandez X., Foran S. K., Adams G. K., 3rd, Kreutner W., Egan R. W., Chapman R. W. Effects of an antibody to interleukin-5 in a monkey model of asthma. Am J Respir Crit Care Med. 1995 Aug;152(2):467–472. doi: 10.1164/ajrccm.152.2.7633694. [DOI] [PubMed] [Google Scholar]
  27. Mauser P. J., Pitman A., Witt A., Fernandez X., Zurcher J., Kung T., Jones H., Watnick A. S., Egan R. W., Kreutner W. Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma. Am Rev Respir Dis. 1993 Dec;148(6 Pt 1):1623–1627. doi: 10.1164/ajrccm/148.6_Pt_1.1623. [DOI] [PubMed] [Google Scholar]
  28. McFadden E. R., Jr, Gilbert I. A. Asthma. N Engl J Med. 1992 Dec 31;327(27):1928–1937. doi: 10.1056/NEJM199212313272708. [DOI] [PubMed] [Google Scholar]
  29. Metzger W. J., Zavala D., Richerson H. B., Moseley P., Iwamota P., Monick M., Sjoerdsma K., Hunninghake G. W. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Description of the model and local airway inflammation. Am Rev Respir Dis. 1987 Feb;135(2):433–440. doi: 10.1164/arrd.1987.135.2.433. [DOI] [PubMed] [Google Scholar]
  30. Mukaida N., Morita M., Ishikawa Y., Rice N., Okamoto S., Kasahara T., Matsushima K. Novel mechanism of glucocorticoid-mediated gene repression. Nuclear factor-kappa B is target for glucocorticoid-mediated interleukin 8 gene repression. J Biol Chem. 1994 May 6;269(18):13289–13295. [PubMed] [Google Scholar]
  31. Peppel K., Vinci J. M., Baglioni C. The AU-rich sequences in the 3' untranslated region mediate the increased turnover of interferon mRNA induced by glucocorticoids. J Exp Med. 1991 Feb 1;173(2):349–355. doi: 10.1084/jem.173.2.349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ponath P. D., Qin S., Ringler D. J., Clark-Lewis I., Wang J., Kassam N., Smith H., Shi X., Gonzalo J. A., Newman W. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest. 1996 Feb 1;97(3):604–612. doi: 10.1172/JCI118456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Resnick M. B., Weller P. F. Mechanisms of eosinophil recruitment. Am J Respir Cell Mol Biol. 1993 Apr;8(4):349–355. doi: 10.1165/ajrcmb/8.4.349. [DOI] [PubMed] [Google Scholar]
  34. Rolfe F. G., Hughes J. M., Armour C. L., Sewell W. A. Inhibition of interleukin-5 gene expression by dexamethasone. Immunology. 1992 Dec;77(4):494–499. [PMC free article] [PubMed] [Google Scholar]
  35. Rothenberg M. E., Luster A. D., Leder P. Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8960–8964. doi: 10.1073/pnas.92.19.8960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rothenberg M. E., Luster A. D., Lilly C. M., Drazen J. M., Leder P. Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung. J Exp Med. 1995 Mar 1;181(3):1211–1216. doi: 10.1084/jem.181.3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rothenberg M. E., Ownbey R., Mehlhop P. D., Loiselle P. M., van de Rijn M., Bonventre J. V., Oettgen H. C., Leder P., Luster A. D. Eotaxin triggers eosinophil-selective chemotaxis and calcium flux via a distinct receptor and induces pulmonary eosinophilia in the presence of interleukin 5 in mice. Mol Med. 1996 May;2(3):334–348. [PMC free article] [PubMed] [Google Scholar]
  38. Schleimer R. P., Bochner B. S. The effects of glucocorticoids on human eosinophils. J Allergy Clin Immunol. 1994 Dec;94(6 Pt 2):1202–1213. doi: 10.1016/0091-6749(94)90333-6. [DOI] [PubMed] [Google Scholar]
  39. Shaver J. R., O'Connor J. J., Pollice M., Cho S. K., Kane G. C., Fish J. E., Peters S. P. Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects. Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 1):1189–1197. doi: 10.1164/ajrccm.152.4.7551369. [DOI] [PubMed] [Google Scholar]
  40. Sousa A. R., Lane S. J., Nakhosteen J. A., Yoshimura T., Lee T. H., Poston R. N. Increased expression of the monocyte chemoattractant protein-1 in bronchial tissue from asthmatic subjects. Am J Respir Cell Mol Biol. 1994 Feb;10(2):142–147. doi: 10.1165/ajrcmb.10.2.8110469. [DOI] [PubMed] [Google Scholar]
  41. Stellato C., Beck L. A., Gorgone G. A., Proud D., Schall T. J., Ono S. J., Lichtenstein L. M., Schleimer R. P. Expression of the chemokine RANTES by a human bronchial epithelial cell line. Modulation by cytokines and glucocorticoids. J Immunol. 1995 Jul 1;155(1):410–418. [PubMed] [Google Scholar]
  42. Wu C. Y., Fargeas C., Nakajima T., Delespesse G. Glucocorticoids suppress the production of interleukin 4 by human lymphocytes. Eur J Immunol. 1991 Oct;21(10):2645–2647. doi: 10.1002/eji.1830211053. [DOI] [PubMed] [Google Scholar]

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