Cyclooxygenase-2 and MicroRNA-155 Expression Are Elevated in Asthmatic Airway Smooth Muscle Cells (original) (raw)

Abstract

Cyclooxygenase-2 (COX-2) expression and PGE 2 secretion from human airway smooth muscle cells (hASMCs) may contribute to b 2-adrenoceptor hyporesponsiveness, a clinical feature observed in some patients with asthma. hASMCs from patients with asthma exhibit elevated expression of cytokine-responsive genes, and in some instances this is attributable to an altered histone code and/or microRNA expression. We hypothesized that COX-2 expression and PGE 2 secretion might be elevated in asthmatic hASMCs in response to proinflammatory signals in part due to altered histone acetylation and/or microRNA expression. hASMCs obtained from nonasthmatic and asthmatic human subjects were treated with cytomix (IL-1b, TNF-a, and IFN-g). A greater elevation of COX-2 mRNA, COX-2 protein, and PGE 2 secretion was observed in the asthmatic cells. We investigated histone H3/H4-acetylation, transcription factor binding, mRNA stability, p38 mitogen-activated protein kinase signaling, and microRNA (miR)-155 expression as potential mechanisms responsible for the differential elevation of COX-2 expression. We found that histone H3/H4-acetylation and transcription factor binding to the COX-2 promoter were similar in both groups, and histone H3/H4-acetylation did not increase after cytomix treatment. Cytomix treatment elevated NF-kB and RNA polymerase II binding to similar levels in both groups. COX-2 mRNA stability was increased in asthmatic cells. MiR-155 expression was higher in cytomix-treated asthmatic cells, and we show it enhances COX-2 expression and PGE 2 secretion in asthmatic and nonasthmatic hASMCs. Thus, miR-155 expression positively correlates with COX-2 expression in the asthmatic hASMCs and may contribute to the elevated expression observed in these cells. These findings may explain, at least in part, b 2-adrenoceptor hyporesponsiveness in patients with asthma.

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References (55)

  1. Hakonarson H, Herrick DJ, Serrano PG, Grunstein MM. Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle. J Clin Invest 1996;97:2593-2600.
  2. Barnes PJ, Pride NB. Dose-response curves to inhaled beta- adrenoceptor agonists in normal and asthmatic subjects. Br J Clin Pharmacol 1983;15:677-682.
  3. Shore SA, Laporte J, Hall IP, Hardy E, Panettieri RA Jr. Effect of IL-1 beta on responses of cultured human airway smooth muscle cells to bronchodilator agonists. Am J Respir Cell Mol Biol 1997;16:702-712.
  4. Laporte JD, Moore PE, Panettieri RA, Moeller W, Heyder J, Shore SA. Prostanoids mediate IL-1b-induced b-adrenergic hyporesponsiveness in human airway smooth muscle cells. Am J Physiol 1998;275:L491-L501.
  5. Guo M, Pascual RM, Wang S, Fontana MF, Valancius CA, Panettieri RA Jr, Tilley SL, Penn RB. Cytokines regulate b-2-adrenergic receptor responsiveness in airway smooth muscle via multiple PKA-and EP2 receptor-dependent mechanisms. Biochemistry 2005;44: 13771-13782.
  6. Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman SI. Cytokines in symptomatic asthma airways. J Allergy Clin Immunol 1992;89:958-967.
  7. Walker C, Bode E, Boer L, Hansel TT, Blaser K, Virchow JC Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis 1992;146:109-115.
  8. Chan V, Burgess JK, Ratoff JC, O'connor BJ, Greenough A, Lee TH, Hirst SJ. Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. Am J Respir Crit Care Med 2006;174:379-385.
  9. Brightling CE, Ammit AJ, Kaur D, Black JL, Wardlaw AJ, Hughes JM, Bradding P. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am J Respir Crit Care Med 2005;171:1103-1108.
  10. John AE, Zhu YM, Brightling CE, Pang L, Knox AJ. Human airway smooth muscle cells from asthmatic individuals have CXCL8 hypersecretion due to increased NF-kappa B p65, C/EBP beta, and RNA polymerase II binding to the CXCL8 promoter. J Immunol 2009; 183:4682-4692.
  11. Chambers LS, Black JL, Ge Q, Carlin SM, Au WW, Poniris M, Thompson J, Johnson PR, Burgess JK. PAR-2 activation, PGE2, and COX-2 in human asthmatic and nonasthmatic airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2003;285:L619-L627.
  12. Burgess JK, Blake AE, Boustany S, Johnson PRA, Armour CL, Black JL, Hunt NH, Hughes JM. CD40 and OX40 ligand are increased on stimulated asthmatic airway smooth muscle. J Allergy Clin Immunol 2005;115:302-308.
  13. Burgess JK, Ge Q, Boustany S, Black JL, Johnson PRA. Increased sensitivity of asthmatic airway smooth muscle cells to prostaglandin E2 might be mediated by increased numbers of E-prostanoid receptors. J Allergy Clin Immunol 2004;113:876-881.
  14. Sousa Ar, Pfister R, Christie PE, Lane SJ, Nasser SM, Schmitz- Schumann M, Lee TH. Enhanced expression of cyclo-oxygenase isoenzyme 2 (COX-2) in asthmatic airways and its cellular distribution in aspirin-sensitive asthma. Thorax 1997;52:940-945.
  15. Wenzel SE, Westcott JY, Smith HR, Larsen GL. Spectrum of prostanoid release after bronchoalveolar allergen challenge in atopic asthmatics and in control groups: an alteration in the ratio of bronchoconstrictive to bronchoprotective mediators. Am Rev Respir Dis 1989;139:450-457.
  16. Nie M, Pang L, Inoue H, Knox AJ. Transcriptional regulation of cyclooxygenase 2 by bradykinin and interleukin-1b in human airway smooth muscle cells: involvement of different promoter elements, transcription factors, and histone h4 acetylation. Mol Cell Biol 2003; 23:9233-9244.
  17. Sato T, Liu X, Nelson A, Nakanishi M, Kanaji N, Wang X, Kim M, Li Y, Sun J, Michalski J, et al. Reduced miR-146a increases prostaglandin E₂in chronic obstructive pulmonary disease fibroblasts. Am J Respir Crit Care Med 2010;182:1020-1029.
  18. Lee H-J, Maeng K, Dang H-T, Kang G-J, Ryou C, Jung JH, Kang H-K, Prchal JT, Yoo E-S, Yoon D. Anti-inflammatory effect of methyl dehydrojasmonate (J2) is mediated by the NF-kB pathway. J Mol Med (Berl) 2011;89:83-90.
  19. Young LE, Moore AE, Sokol L, Meisner-Kober N, Dixon DA. The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2. Mol Cancer Res 2012;10:167-180.
  20. Coward WR, Watts K, Feghali-Bostwick CA, Knox A, Pang L. Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis. Mol Cell Biol 2009;29:4325-4339.
  21. John AE, Clifford RL, Brightling CE, Knox AJ. Basal hypersecretion of CXCL8 in asthmatic human airway smooth muscle cells is associated with increased binding of histone acetyltransferases to the CXCL8 promoter and acetylation of histone H3 [abstract].
  22. Am J Respir Crit Care Med 2010;181:A2145.
  23. Jude JA, Dileepan M, Subramanian S, Solway J, Panettieri RA Jr, Walseth TF, Kannan MS. miR-140-3p regulation of TNF-a-induced CD38 expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2012;303:L460-L468.
  24. Singer CA, Baker KJ, McCaffrey A, AuCoin DP, Dechert MA, Gerthoffer WT. p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Am J Physiol Lung Cell Mol Physiol 2003; 285:L1087-L1098.
  25. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008;3:1101-1108.
  26. Clifford RL, John AE, Brightling CE, Knox AJ. Abnormal histone methylation is responsible for increased vascular endothelial growth factor 165a secretion from airway smooth muscle cells in asthma. J Immunol 2012;189:819-831.
  27. Hedges JC, Singer CA, Gerthoffer WT. Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am J Respir Cell Mol Biol 2000;23:86-94.
  28. Pang L, Knox AJ. Effect of interleukin-1 b, tumour necrosis factor-a and interferon-g on the induction of cyclo-oxygenase-2 in cultured human airway smooth muscle cells. Br J Pharmacol 1997;121:579-587.
  29. Belvisi MG, Saunders MA, Haddad el-B, Hirst SJ, Yacoub MH, Barnes PJ, Mitchell JA. Induction of cyclo-oxygenase-2 by cytokines in human cultured airway smooth muscle cells: novel inflammatory role of this cell type. Br J Pharmacol 1997;120:910-916.
  30. Bhattacharyya S, Balakathiresan NS, Dalgard C, Gutti U, Armistead D, Jozwik C, Srivastava M, Pollard HB, Biswas R. Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8. J Biol Chem 2011;286:11604-11615.
  31. Xu C, Ren G, Cao G, Chen Q, Shou P, Zheng C, Du L, Han X, Jiang M, Yang Q, et al. miR-155 regulates immune modulatory properties of mesenchymal stem cells by targeting TAK1-binding protein 2. J Biol Chem 2013;288:11074-11079.
  32. Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, Redmond TM. Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochem Biophys Res Commun 2010;402: 390-395.
  33. Xia YC, Redhu NS, Moir LM, Koziol-White C, Ammit AJ, Al-Alwan L, Camoretti-Mercado B, Clifford RL. Pro-inflammatory and immunomodulatory functions of airway smooth muscle: emerging concepts. Pulm Pharmacol Ther 2013;26:64-74.
  34. Jenuwein T, Allis CD. Translating the histone code. Science 2001;293: 1074-1080.
  35. Keslacy S, Tliba O, Baidouri H, Amrani Y. Inhibition of tumor necrosis factor-a-inducible inflammatory genes by interferon-g is associated with altered nuclear factor-kappaB transactivation and enhanced histone deacetylase activity. Mol Pharmacol 2007;71:609-618.
  36. Dixon DA, Blanco FF, Bruno A, Patrignani P. Mechanistic aspects of COX-2 expression in colorectal neoplasia. Recent Results Cancer Res 2013;191:7-37.
  37. Gerthoffer WT, Singer CA. MAPK regulation of gene expression in airway smooth muscle. Respir Physiol Neurobiol 2003;137:237-250.
  38. Brook M, Tchen CR, Santalucia T, McIlrath J, Arthur JSC, Saklatvala J, Clark AR. Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol 2006;26:2408-2418.
  39. Dean JL, Brook M, Clark AR, Saklatvala J. p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem 1999;274:264-269.
  40. Clark AR, Dean JLE, Saklatvala J. Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett 2003;546:37-44.
  41. Akhtar N, Haqqi TM. MicroRNA-199a* regulates the expression of cyclooxygenase-2 in human chondrocytes. Ann Rheum Dis 2012;71: 1073-1080.
  42. Bala S, Marcos M, Kodys K, Csak T, Catalano D, Mandrekar P, Szabo G. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor alpha (TNFalpha) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem 2011;286:1436-1444.
  43. Malmh äll C, Alawieh S, Lu Y, Sj östrand M, Bossios A, Eldh M, R ådinger M. MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung. J Allergy Clin Immunol 2014; 133:1429-1438.
  44. Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res 2008;36: D149-D153.
  45. O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA 2009;106:7113-7118.
  46. Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF, Wang ED. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res 2010;70:3119-3127.
  47. Wang P, Hou J, Lin L, Wang C, Liu X, Li D, Ma F, Wang Z, Cao X. Inducible microRNA-feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol 1950;2010:6226-6233.
  48. Yang C-M, Lee I-T, Lin C-C, Yang Y-L, Luo S-F, Kou YR, Hsiao L-D. Cigarette smoke extract induces COX-2 expression via a PKCalpha/ c-Src/EGFR, PDGFR/PI3K/Akt/NF-kappaB pathway and p300 in tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2009;297:L892-L902.
  49. Sheng H, Shao J, Dubois RN. K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. Cancer Res 2001;61:2670-2675.
  50. Schmidlin M, Lu M, Leuenberger SA, Stoecklin G, Mallaun M, Gross B, Gherzi R, Hess D, Hemmings BA, Moroni C. The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B. EMBO J 2004;23:4760-4769.
  51. Gherzi R, Trabucchi M, Ponassi M, Ruggiero T, Corte G, Moroni C, Chen C-Y, Khabar KS, Andersen JS, Briata P. The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling. PLoS Biol 2006;5:e5.
  52. Bai TR. Abnormalities in airway smooth muscle in fatal asthma. Am Rev Respir Dis 1990;141:552-557.
  53. Comer BS, Chen B, Camoretti-Mercado B, Halayko AJ, Solway J, Gerthoffer WT. Cytokine-induced cyclooxygenase-2 expression and prostaglandin E2 secretion are increased in asthmatic human airway smooth muscle [abstract].
  54. Am J Respir Crit Care Med 2013;187: A2298.
  55. Comer BS. Cyclooxygenase-2 expression in asthmatic human airway smooth muscle cells. [Ph.D. thesis.] Mobile, AL: University of South Alabama; 2013.