摘要
第一部分:红霉素对香烟烟雾刺激的人巨噬细胞释放炎症介质的影响的实验研究
目的(一)探讨香烟烟雾诱导人巨噬细胞产生炎症反应的分子学机制。(二)从抗炎的角度来探讨红霉素(EM)对香烟烟雾诱导的人巨噬细胞释放炎症介质的影响。
方法体外培养人类单核细胞系U937细胞,用佛波脂(PMA,10ng/ml)将其诱导分化为人巨噬细胞。按传统方法制备好香烟烟雾提取物(CSE)用于实验。将传代后的细胞分组:①对照组,②CSE组(加入1%CSE孵育24h),③红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h)。采用酶联免疫吸附试验(ELISA)检测细胞培养上清液的细胞因子白介素-8(IL-8)和肿瘤坏死因子-α(TNF-а)的浓度。数据用均数±标准差(?x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一) 1%CSE刺激人巨噬细胞24小时后,与对照组比较,巨噬细胞释放IL-8的含量(ng/L: CSE组281.53±89.98,对照组217.82±83.01;n=7,P <0.05;)和TNF-а的含量(pg/mL: CSE组729.25±44.17,对照组316.60±224.89;n=6,P <0.05;)均明显增高。
(二)红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,与CSE组比较,巨噬细胞释放IL-8的含量(ng/L: CSE+EM组203.14±95.77,CSE组281.53±89.98;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE+EM组510.29±309.83,CSE组281.53±89.98;n=6,P<0.05)均明显下降。
结论香烟烟雾通过刺激人巨噬细胞释放IL-8和TNF-а等炎症介质引起炎症,这提示是香烟烟雾引起炎症的机制之一。红霉素对香烟烟雾所导致的炎症起重要的调控作用(抑制作用),其作用部分是通过对炎性细胞因子IL-8和TNF-α的抑制而实现的,这是红霉素抗炎作用机制之一。
第二部分:红霉素对香烟烟雾刺激的人巨噬细胞核因子-κB活性的影响的实验研究
目的(一)探讨香烟烟雾对人巨噬细胞核转录因子核因子-κB(NF-κB)活性的影响及其与炎症介质的关系。(二)从抗炎的角度来探讨红霉素对香烟烟雾刺激的人巨噬细胞NF-κB活性的影响。
方法体外培养人类单核细胞系U937细胞,用PMA将其诱导分化为人巨噬细胞。按传统方法制备好CSE用于实验。将传代后的细胞分组:①对照组,②CSE组(加入1%CSE孵育24h),③红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h),④吡咯烷二硫氨基甲酸(PDTC)组(加入20nM PDTC预孵育24h后,加入1%CSE继续孵育24h)。细胞提取核蛋白,采用电泳迁移率改变分析法(EMSA)检测NF-κB的活性。采用ELISA法检测细胞上清液IL-8的浓度。数据用均数±标准差(x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一)1%CSE刺激人巨噬细胞24小时后,巨噬细胞核转录因子NF-κB活性显著增强。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,NF-κB活性被抑制;当红霉素预孵育时间延长至48小时,NF-κB活性被抑制更明显。作为阴性对照组,NF-κB的特异性抑制剂PDTC组的NF-κB活性明显被抑制。
(二)1%CSE刺激人巨噬细胞24小时后,细胞释放IL-8含量增高(ng/L: CSE组264.93±14.89,对照组103.52±3.33;n=6,P <0.05)。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,细胞释放IL-8含量下降(ng/L: CSE+EM组196.70±14.13,CSE组264.93±14.89;n=6,P <0.05)。NF-κB特异性抑制剂PDTC抑制香烟烟雾刺激的人巨噬细胞释放IL-8的含量(ng/L: PDTC组95.06±5.86,CSE组264.93±14.89;n=6,P <0.05)。
结论实验结果提示香烟烟雾诱导人巨噬细胞发生炎症的分子学机制之一是通过激活巨噬细胞的核转录因子NF-κB继而促使炎症介质IL-8的释放实现的。红霉素抑制香烟烟雾诱导的炎症的途径之一是通过抑制NF-κB活性从而抑制炎症细胞因子IL-8的表达,这是红霉素抗炎作用的部分分子学机制之一。
第三部分:红霉素对香烟烟雾刺激的人巨噬细胞核组蛋白去乙酰化酶表达的影响的实验研究
目的(一)探讨香烟烟雾对人巨噬细胞组蛋白去乙酰化酶(HDAC)表达的影响及其与NF-κB,炎症介质的关系。(二)从抗炎的角度来探讨红霉素对香烟烟雾刺激的人巨噬细胞HDAC总活性和HDAC1,2,3蛋白表达的影响其与NF-κB,炎症介质的关系。
方法体外培养人类单核细胞系U937细胞,用PMA将其诱导分化为人巨噬细胞。按传统方法制备好CSE用于实验。将传代后的细胞分组:对照组、CSE组(加入1%CSE孵育24h)、红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h)、HDAC的特异性抑制剂曲古霉素(TSA)组(加入TSA100ng/ml孵育24h),细胞提取核蛋白,采用比色法检测细胞HDAC活性和Western blot法检测细胞HDAC1,HDAC2,和HDAC3和NF-κB蛋白表达。采用ELISA法检测细胞培养上清液的细胞因子IL-8和TNF-а的浓度。数据用均数±标准差(x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一)1%CSE刺激人巨噬细胞24小时后,巨噬细胞释放IL-8的含量(ng/L: CSE组281.53±89.98,对照组217.82±83.01;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE组729.25±444.17,对照组316.60±224.89;n=7,P <0.05;)均明显增高。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,巨噬细胞释放IL-8的含量(ng/L: CSE+EM组203.14±95.77,CSE组281.53±89.98;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE+EM组510.29±309.83,CSE组281.53±89.98;n=7,P <0.05)均明显下降。此外,HDAC的特异性抑制剂TSA组的人巨噬细胞释放IL-8的含量(ng/L: TSA组232.21±109.67,对照组217.82±83.01;n=7,P <0.05)和TNF-а的含量(pg/mL: TSA组428.71±371.00,对照组316.60±224.89;n=7,P <0.05)均明显升高。
(二)1%CSE刺激人巨噬细胞24小时后,与阳性对照组比较,巨噬细胞HDAC总活性明显减弱(微摩尔对硝基苯/分钟: CSE组0.0803±0.0431,阳性对照组0.2455±0.0595;n=4,P <0.05)。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,与CSE组比较,巨噬细胞HDAC总活性增强(微摩尔对硝基苯/分钟: CSE+EM组0.0865±0.05081,CSE组0.0803±0.0431;n=4,P <0.05)。作为阴性对照组,HDAC的特异性抑制剂TSA组的HDAC总活性被抑制。
(三)1%CSE刺激人巨噬细胞24小时后,与对照组比较,巨噬细胞HDAC1,2,3表达水平均下降,以HDAC2改变明显。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,与CSE组比较,巨噬细胞HDAC1,2,3表达均增强,以HDAC2改变明显。作为阴性对照组,HDAC的特异性抑制剂TSA组的HDAC1,2,3表达明显被抑制。
(四) 1%CSE刺激巨噬细胞24小时后,细胞NF-КB蛋白表达增强。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,细胞NF-КB蛋白表达水平下降。HDAC的特异性抑制剂TSA组细胞的NF-КB蛋白表达增强。
结论实验结果提示香烟烟雾诱导人巨噬细胞发生炎症的分子学机制之一是通过抑制巨噬细胞HDAC活性和HDAC1,HDAC2和HDAC3蛋白表达水平(尤其是HDAC2水平)继而激活NF-кB,使NF-кB蛋白表达增加,促使炎症介质的释放实现的。红霉素通过提高HDAC活性及HDAC1,2,3,特别是HDAC2蛋白表达,继而抑制NF-κB的活性和蛋白表达从而抑制炎症基因表达,下调炎症反应,这一机制是红霉素具有免疫调节和抗炎作用的分子学机制之一。
Chapter 1
Effect of Erythromycin on the release of proinflammatory cytokines induced by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin (EM) on proinflammatory cytokine induced by CSE in human macrophages.
Methods:
The Aqueous cigarette smoke extract (CSE) was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment for 24 h at 37°C with 5% CO2. The levels of interleukin-8 (IL-8) and tumor necrosis factor-а(TNF-а) release in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions.
Results:
CSE 1% treatment significantly increased IL-8 release (ng/L: CSE1% 281.53±89.98, controls 217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: CSE1% 729.25±444.17, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. To find out the role of EM on CSE-mediated proinflammatory cytokine release, we pretreated macrophages with EM for 24 h and then washed cells, then incubated with CSE 1% for 24 h. EM significantly inhibited CSE-mediated IL-8 release (ng/L: CSE1% 281.53±89.98, CSE1% + EM1μg/ml 203.144±95.77, n=7, P<0.05) and TNF-аrelease (pg/ml: CSE1% 729.25±444.17, CSE1% + EM1μg/ml 510.29±309.83, n=6, P<0.05).
Conclusions:
Our studies show that cigarette smoke induces an inflammatory response by driving proinflammatory gene transcription and stimulating the release of proinflammatory cytokines in human macrophages. EM is able to decrease CSE-induced release of proinflammatory cytokines, such as IL-8 and TNF-а. This suggests that EM protects against the proinflammatory effects of CSE in macrophages cells.
Chapter 2
Effect of Erythromycin on the transcriptional activity of NF-КB activated by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin on the transcriptional activity of nuclear factor-КB (NF-КB) activated by cigarette smoke in human macrophages cells.
Methods:
The Aqueous CSE was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using PMA according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment , and NF-КB inhibitor pyrrolidine dithiocarbamate (PDTC) for 24 h at 37°C with 5% CO2. NF-КB was assessed by electrophoretic mobility-shift assay(EMSA). Briefly, nuclear extracts were prepared according to a method described previously. Protein concentration was determined by the Bradford method. EMSA was done with the Gel-Shift Assay System following the manufacturer′s instructions. The levels of IL-8 release in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions.
Results:
Treatment with CSE1% for 24h increased NF-КB nuclear binding and IL-8 release in human macrophage cells. EM pretreatment has inhibitory effect on CSE-induced NF-КB transcription activity and IL-8 release in human macrophage cells. As a negative control, PTDC inhibit NF-КB activation and IL-8 release.
Conclusions:
Our data show that cigarette smoke induces an inflammatory response by activating transcription factor NF-КB in human macrophages cells, which maybe results in increasing IL-8 release. EM has an anti-inflammatory action, presumably via an interaction with the NF-КB signaling pathway. Our data suggest that Erythromycin inhibited NF-КB transcriptional activity resulting in decreasing cigarette smoke-induced IL-8 release to exert anti-inflammatory effect.
Chapter 3
Effect of Erythromycin on Histone Deacetylase Activity Decreased by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin on histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein expression, correlation with NF-КB expression and inflammatory mediators release in human macrophages cells.
Methods:
The Aqueous CSE was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using PMA according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment , and HDAC inhibitor trichostatin A (TSA; 100 ng/ml) for 24 h at 37°C with 5% CO2. The levels of IL-8 and TNF-аrelease in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions. And the HDAC activity was measured with a colorimetric assay kit and Western Blot was used for HDAC1, 2, 3 and NF-КB protein assays.
Results:
1. CSE 1% treatment significantly increased IL-8 release (ng/L: CSE1% 281.53±89.98, controls 217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: CSE1% 729.25±444.17, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. Pretreatment with EM significantly inhibited CSE-mediated IL-8 release (ng/L: CSE1% 281.53±89.98, CSE1% + EM1μg/ml 203.144±95.77, n=7, P<0.05) and TNF-аrelease (pg/ml: CSE1% 729.25±444.17, CSE1% + EM1μg/ml 510.29±309.83, n=6, P<0.05). Further, TSA treatment significantly increased IL-8 release (ng/L: TSA 232.21±109.67, controls217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: TSA 428.71±371.00, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. 2. CSE 1% significantly decreased HDAC activity and HDAC1, 2, 3 protein levels at 24h, which were associated with the increased protein expression of NF-КB. We also showed that CSE-mediated inhibition of HDAC activity and HDAC1, 2, 3 protein levels and increase of NF-КB protein expression were restored by EM pretreatment at 24h . We further showed that CSE particularly decreased HDAC2 protein level, which was significantly restored by EM pretreatment. As a positive control, TSA decreased HDAC activity and HDAC1, -2, and -3 protein levels and increased NF-КB protein expression.
Conclusions:
Cigarette smoke reduced HDAC expression and decreased the protein levels of HDAC1, HDAC2 and HDAC3 in human macrophages cells. Particularly, cigarette smoke caused a decline in HDAC2 protein expression. The decrease of HDAC activity and HDAC1, 2, 3 expression may be responsible for the increased inflammatory gene transcription. EM is able to restore HDAC activity and HDAC1, HDAC2, HDAC3 levels decreased by cigarette smoke and inhibite NF-КB activity resulting in decreasing CSE-mediated IL-8 and TNF-аrelease, which has shown an important explanation that EM possess the anti-inflammatory effect induced by cigarette smoke.
引文
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6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
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4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
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2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
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11. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
12. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
13. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
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