Effects of Histone Modification on Chemokines Expression in Alveolar Epithelial TypeⅡ Cells in a RatModel of COPD_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

GAN Lixing , LI Chengye , GUO Xuejun.

Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong University School of Medicine. Shanghai,200092, ChinaCorresponding Author: GUO Xue-jun, E-mail: guoxjz@ yahoo. com. cn;

Corresponding author：

Keywords：

Chronic obstructive pulmonary disease; Alveolar epithelial typeⅡ cell; Histone deacetylase; Chemokine

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Objective To investigate the effects of histone modification on the expression of chemokines in alveolar epithelial typeⅡ cells ( AECⅡ) in a rat model of chronic obstructive pulmonary disease ( COPD) . Methods 20 SD rats were randomly assigned to a normal control group and a COPD group. The rat model of COPD was established by cigarette smoking. Lung histological changes were observed by HE staining. AECⅡ cells were isolated and identified by alkaline phosphatase staining and electron microscopic. The mRNA expressions of monocyte chemoattractant protein ( MCP) -1, IL-8, and macrophage inflammatory protein ( MIP) -2αwere detected by real-time quantitative PCR. The expression of histone deacetylase ( HDAC) 2 was measured by western blot. Chromatin immunoprecipitation ( ChIP) was used to
detect H3 and H4 acetylation, and H4K9 methylation in the promoter region of chemokine gene. Results Compared with the control group, the mRNA expressions of MCP-1, IL-8, and MIP-2αin the COPD group increased 4. 48,3. 14, and 2. 83 times, respectively. The expression of HDAC2 protein in the COPD group was
significantly lower than in the control group ( 0. 25 ±0. 15 vs. 0. 66 ±0. 15, P lt; 0. 05) . The expression of HDAC2 had a negative correlation with the gene expressions of IL-8, MCP-1, and MIP-2α( r = - 0. 960,- 0. 914, - 0. 928, respectively, all P lt;0. 05) . The levels of H3 and H4 acetylation were higher, and H4K9 methylation level was lower in the promoter region of chemokine gene in the COPD group compared with the control group ( all P lt; 0. 05) . Conclusions MCP-1, IL-8, and MIP-2α participate and promote the lung inflammatory response in COPD. HDAC2-mediated histone modification may play an important role in COPD inflammation.

Citation： GAN Lixing,LI Chengye,GUO Xuejun.. Effects of Histone Modification on Chemokines Expression in Alveolar Epithelial TypeⅡ Cells in a RatModel of COPD. Chinese Journal of Respiratory and Critical Care Medicine, 2010, 9(4): 360-364. doi: Copy

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6.	张斌, 何威, 杨扬, 等. 体外培养人皮肤鳞状细胞癌A431 细胞Smad2 和Smad3 mRNA 的表达. 临床皮肤科杂志, 2008, 37: 290 -292.
7.	Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol, 2000, 20: 6891 -6903.
8.	Ashburner BP, Westerheide SD, Baldwin AS Jr. The p65 ( RelA)subunit of NF- κB interacts with the histone deacetylase ( HDAC)corepressors HDAC1 and HDAC2 to negatively regulate gene expression.Mol Cell Biol, 2001 , 21: 7065-7077.
9.	Ito K, Adcock IM. Histone acetylation and histone deacetylation.Mol Biotechnol, 2002 , 20: 99-106 .
10.	Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J, 2007, 29: 1224-1238.
11.	Szulakowski P, Crowther AJL, Jimenez LA, et al. The effect of smoking on the transcriptional regulation of lung inflammation inpatients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2006, 174: 41-50.
12.	Rajendrasozhan S, Yang SR, Edirisinghe I, et al. Deacetylases and NF-kappaB in redox regulation of cigarette smoke-induced lung inflammation: epigenetics in pathogenesis of COPD. Antioxid Redox Signal, 2008, 10: 799-812 .
13.	Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol, 2009, 71 : 451-464.
14.	Ito K, Yamamura S, Essilfie-Quaye S, et al. Histone deacetylase 2 -mediated deacetylation of the glucocorticoid receptor enables NFkappaB suppression. J Exp Med, 2006, 203: 7-13.

1. Adcock IM, Tsaprouni L, Bhavsar P, et al. Epigenetic regulation of airway inflammation. Curr Opin Immunol, 2007 , 19: 694 -700.
2. 田素增, 谢敏, 刘涛, 等. 慢性阻塞性肺疾病大鼠Ⅱ 型肺泡上皮细胞凋亡水平的变化及吸入糖皮质激素对其的影响. 中国呼吸与危重监护杂志, 2007, 6 : 381-384.
3. Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory disease. Lancet, 2009, 373: 1905-1917.
4. Dobbs LG, Williams MC. An improved method for isolating typeⅡcells in high yield and purity. Rev Rispir Dis, 1986, 134 : 141-145.
5. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real -time quantitative PCR and the 2 ( -Delta Delta C( T) ) .Methods, 2001 , 25: 402-408.
6. 张斌, 何威, 杨扬, 等. 体外培养人皮肤鳞状细胞癌A431 细胞Smad2 和Smad3 mRNA 的表达. 临床皮肤科杂志, 2008, 37: 290 -292.
7. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol, 2000, 20: 6891 -6903.
8. Ashburner BP, Westerheide SD, Baldwin AS Jr. The p65 ( RelA)subunit of NF- κB interacts with the histone deacetylase ( HDAC)corepressors HDAC1 and HDAC2 to negatively regulate gene expression.Mol Cell Biol, 2001 , 21: 7065-7077.
9. Ito K, Adcock IM. Histone acetylation and histone deacetylation.Mol Biotechnol, 2002 , 20: 99-106 .
10. Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J, 2007, 29: 1224-1238.
11. Szulakowski P, Crowther AJL, Jimenez LA, et al. The effect of smoking on the transcriptional regulation of lung inflammation inpatients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2006, 174: 41-50.
12. Rajendrasozhan S, Yang SR, Edirisinghe I, et al. Deacetylases and NF-kappaB in redox regulation of cigarette smoke-induced lung inflammation: epigenetics in pathogenesis of COPD. Antioxid Redox Signal, 2008, 10: 799-812 .
13. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol, 2009, 71 : 451-464.
14. Ito K, Yamamura S, Essilfie-Quaye S, et al. Histone deacetylase 2 -mediated deacetylation of the glucocorticoid receptor enables NFkappaB suppression. J Exp Med, 2006, 203: 7-13.

Chinese Journal of Respiratory and Critical Care Medicine

Effects of Histone Modification on Chemokines Expression in Alveolar Epithelial TypeⅡ Cells in a RatModel of COPD

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