Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells

Respiratory Research

Reen Wu²  Nicholas J Kenyon²  Phil Thai²  Amir A Zeki¹ 

[1] Genomics & Biomedical Sciences Facility (GBSF), 451 Health Sciences Drive, Suite #6510, Davis, CA, 95616, USA;U.C. Davis, School of Medicine, U.C. Davis Medical Center, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Center for Comparative Respiratory Biology & Medicine, Davis, CA, USA

关键词: Mouse tracheal epithelium;    Gene expression;    Chemokines;    Cytokines;    HMG-CoA reductase;    Airway epithelium;    Mevalonate pathway;    Asthma;    Statin;   

Others  :  796724
DOI  :  10.1186/1465-9921-13-38

 received in 2012-02-08, accepted in 2012-05-14,  发布年份 2012

【 摘 要 】

Background

Asthma causes significant morbidity worldwide in adults and children alike, and incurs large healthcare costs. The statin drugs, which treat hyperlipidemia and cardiovascular diseases, have pleiotropic effects beyond lowering cholesterol, including immunomodulatory, anti-inflammatory, and anti-fibrotic properties which may benefit lung health. Using an allergic mouse model of asthma, we previously demonstrated a benefit of statins in reducing peribronchiolar eosinophilic inflammation, airway hyperreactivity, goblet cell hyperplasia, and lung IL-4 and IL-13 production.

Objectives

In this study, we evaluated whether simvastatin inhibits IL-13-induced pro-inflammatory gene expression of asthma-related cytokines in well-differentiated primary mouse tracheal epithelial (MTE) cell cultures. We hypothesized that simvastatin reduces the expression of IL-13-inducible genes in MTE cells.

Methods

We harvested tracheal epithelial cells from naïve BALB/c mice, grew them under air-liquid interface (ALI) cell culture conditions, then assessed IL-13-induced gene expression in MTE cells using a quantitative real-time PCR mouse gene array kit.

Results

We found that simvastatin had differential effects on IL-13-mediated gene expression (inhibited eotaxin-1; MCP-1,-2,-3; and osteopontin (SPP1), while it induced caspase-1 and CCL20 (MIP-3α)) in MTE cells. For other asthma-relevant genes such as TNF, IL-4, IL-10, CCL12 (MCP-5), CCL5 (RANTES), and CCR3, there were no significant IL-13-inducible or statin effects on gene expression.

Conclusions

Simvastatin modulates the gene expression of selected IL-13-inducible pro-inflammatory cytokines and chemokines in primary mouse tracheal epithelial cells. The airway epithelium may be a viable target tissue for the statin drugs. Further research is needed to assess the mechanisms of how statins modulate epithelial gene expression.

【 授权许可】

   
2012 Zeki et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Liao JK, Laufs U: Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005, 45:89-118.
• [2]Greenwood J, Steinman L, Zamvil SS: Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006, 6(5):358-370.
• [3]Alexeeff SE, Sparrow D, Vokonas PS, Schwartz J: Statin use reduces decline in lung function: VA Normative Aging Study. Am J Respir Crit Care Med 2007, 176:742-747.
• [4]Mancini GB, Zhang B, Levesque LE, FitzGerald JM, Brophy JM: Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006, 47(12):2554-2560.
• [5]Ishida W, Ishii M, Fujiwara F, Taneichi H, Takebe N, Takahashi K, Kaneko Y, Segawa I, Kajiwara T, Inoue H, Satoh J: Decrease in Mortality Rate of Chronic Obstructive Pulmonary Disease (COPD) with Statin Use: A Population-Based Analysis in Japan. J Exp Med 2007, 212(3):265-273.
• [6]Young RP, Hopkins R, Eaton TE: Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence. Postgrad Med J 2009, 85(1006):414-421.
• [7]Blamoun AI, DeBari VA, Rashid AO, Sheikh M, Khan MA: Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract 2008, 62(9):1373-1378.
• [8]Hothersall EJ, Chaudhuri R, McSharry C, et al.: Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma. Thorax 2008, 63(12):1070-1075.
• [9]Maneechotesuwan K, Ekjiratrakul W, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ: Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2,3-dioxygenase. J Allergy Clin Immunol 2010, 126(4):754-762.
• [10]Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR: Simvastatin in the treatment of asthma: lack of steroid-sparing effect. Thorax 2010, 65(10):891-896.
• [11]Zeki AA, Franzi L, Last J, Kenyon NJ: Simvastatin Inhibits Airway Hyperreactivity: Implications for the Mevalonate Pathway and Beyond. Am J Respir Crit Care Med 2009, 180:731-740.
• [12]Zeki AA, Bratt JM, Rabowsky M, Last JA, Kenyon NJ: Simvastatin inhibits goblet cell hyperplasia and lung arginase in a mouse model of allergic asthma: A novel treatment for airway remodeling? Transl Res 2010, 156(6):335-349.
• [13]Ou XM, Wen FQ, Feng YL, Huang XY, Xiao J: Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats. Chin Med J 2008, 121(17):1680-1687.
• [14]Vukelic S, Stojadinovic O, Pastar I, et al.: Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. J Biol Chem 2010, 285(3):1980-1988.
• [15]Murphy DM, Corris PA, Johnson GE, Small T, Jones D, Fisher AJ, Egan JJ, Cawston TE, Ward C, Lordan JL: Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients. Am J Physiol Lung Cell Mol Physiol 2008, 294:592-599.
• [16]Wang W, Le W, Ahuja R, Cho DY, Hwang PH, Upadhyay D: Inhibition of Inflammatory Mediators: Role of Statins in Airway Inflammation. Otolaryngol Head Neck Surg 2011, 144(6):982-987.
• [17]Sakoda K, Yamamato M, Negishi Y, Liao JK, Node K, Izumi Y: Simvastatin decreases IL-6 and IL-8 production in epithelial cells. J Dent Res 2006, 85(6):520-523.
• [18]Wu S, Duan S, Zhao S, Cai Y, Chen P, Fang X: Atorvastatin reduces lipopolysaccharide-induced expression of cyclooxygenase-2 in human pulmonary epithelial cells. Respir Res 2005, 6:27. BioMed Central Full Text
• [19]Sakamoto N, Hayashi S, Mukae H, Vincent R, Hogg JC, van Eeden SF: Effect of atorvastatin on PM10-induced cytokine production by human alveolar macrophages and bronchial epithelial cells. Int J Toxicol 2009, 28(1):17-23.
• [20]Kreiselmeier NE, Kraynack NC, Corey DA, Kelley TJ: Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells. Am J Physiol Lung Cell Mol Physiol 2003, 285(6):L1286-L1295.
• [21]Iwata A, Shirai R, Ishii H, et al.: Inhibitory Effect of Statins on Inflammatory Cytokine Production from Human Bronchial Epithelial Cells. Clin Exp Immunol 2012, 168(2):234-240.
• [22]Kraynack NC, Corey DA, Elmer HL, Kelley TJ: Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2002, 283(3):L604-L611.
• [23]Robinson CB, Wu R: Culture of Conducting Airway Epithelial in Serum-Free Medium. J Tissue Cult Meth 1991, 13(20):95-102.
• [24]Wu R, Nolan E, Turner C: Expression of tracheal differentiated functions in serum-free hormone-supplemented medium. J Cell Physiol 1985, 125(2):167-181.
• [25]You Y, Richer EJ, Huang T, Brody SL: Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. Am J Physiol Lung Cell Mol Physiol 2002, 283(6):L1315-L1321.
• [26]McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY: A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 2004, 172(5):2903-2908.
• [27]Kim DY, Ryu SY, Lim JE, Lee YS, Ro JY: Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model. Eur J Pharmacol 2007, 557:76-86.
• [28]Ahmad T, Mabalirajan U, Sharma A, et al.: Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from asymmetric dimethyl-arginine to asthma. Am J Respir Cell Mol Biol 2011, 44(4):531-539.
• [29]Holgate ST: Epithelium dysfunction in asthma. J Allergy Clin Immunol 2007, 120:1233-1244.
• [30]Holgate ST: The Airway Epithelium is Central to the Pathogenesis of Asthma. Allergol Int 2008, 57:1-10.
• [31]Konno S, Kurokawa M, Uede T, Nishimura M, Huang S-K: Role of osteopontin, a multifunctional protein, in allergy and asthma. Clin Exp Allergy Rev 2011, 41(10):1360-1366.
• [32]Schneider DJ, Lindsay JC, Zhou Y, Molina JG, Blackburn MR: Adenosine and osteopontin contribute to the development of chronic obstructive pulmonary disease. FASEB 2010, 24(1):70-80.
• [33]Sabo-Attwood T, Ramos-Nino ME, Eugenia-Ariza M, et al.: Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis. Am J Pathol 2011, 178(5):1975-1985.
• [34]Samitas K, Zervas E, Vittorakis S, et al.: Osteopontin expression and relation to disease severity in human asthma. Eur Respir J 2011, 37(2):331-341.
• [35]Delimpoura V, Bakakos P, Tseliou E, et al.: Increased levels of osteopontin in sputum supernatant in severe refractory asthma. Thorax 2010, 65(9):782-786.
• [36]Simoes DCM, Xanthou G, Petrochilou K, Panoutsakopoulou V, Roussos C, Gratziou C: Osteopontin deficiency protects against airway remodeling and hyperresponsiveness in chronic asthma. Am J Respir Crit Care Med 2009, 179(10):894-902.
• [37]Xanthou G, Alissafi T, Semitekolou M, et al.: Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets. Nat Med 2007, 13(5):570-578.
• [38]Hoover DM, Boulegue C, Yang D, Oppenheim JJ, Tucker K, Lu W, Lubkowski J: The structure of human macrophage inflammatory protein-3a/CCL20. Linking antimicrobial and CC chemokine receptor-6-binding activities with human b-defensins. J Biol Chem 2002, 277(40):37647-37654.
• [39]Yang D: Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 2003, 74(3):448-455.
• [40]Shimada K, Crother TR, Karlin J, et al.: Caspase-1 dependent IL-1β secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection. PLoS One 2011, 6(6):e21477.
• [41]Thomas PG, Dash P, Aldridge JR, et al.: The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 2009, 30(4):566-575.
• [42]Kumar S: Caspases and their many biological functions. Cell Death Differ 2006, 14(1):1-2.
• [43]Imamura M, Okunishi K, Ohtsu H, Nakagome K, Harada H, Tanaka R, Yamamoto K, Dohi M: Pravastatin attenuates allergic airway inflammation by suppressing antigen sensitization, interleukin 17 production and antigen presentation in the lung. Thorax 2009, 64:44-49.
• [44]Fessler MB, Jeyaseelan S, Lieber JG, Arndt PG, Nick JA, Worthen GS, Young SK: A role for hydroxy methylglutaryl coenzyme A reductase in pulmonary inflammation and host defense. Am J Respir Crit Care Med 2005, 171(6):606-615.
• [45]Y-Juan C, Chen P, Wang H-Xia, et al.: Simvastatin attenuates acrolein-induced mucin production in rats: Involvement of the Ras / extracellular signal-regulated kinase pathway. Int Immunopharmacol 2010, 10(6):685-693.
• [46]Barnes PJ: The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest 2008, 118(11):3546-3556.
• [47]Anderson GP: Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008, 372(9643):1107-1119.
• [48]Cho S-H, Stanciu L, Holgate ST, Johnston SL: Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD4+ and CD8+ T cells in atopic asthma. Am J Respir Crit Care Med 2005, 171(3):224-230.
• [49]Dvorak A, Tilley AE, Shaykhiev R, Wang R, Crystal RG: Do airway epithelium air-liquid cultures represent the in vivo airway epithelium transcriptome? Am J Respir Cell Mol Biol 2011, 44(4):465-473.
• [50]Hirota J, Hackett T-L, Inman MD, Knight D: Modeling asthma in mice: what have we learned about the airway epithelium? Am J Respir Cell Mol Biol 2011, 44(4):431-438.