肺炎衣原体诱导THP-1源性泡沫细胞形成的机制
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摘要
第一部分肺炎衣原体感染对THP-1源性泡沫细胞形成的影响
背景胆固醇酯在巨噬细胞内过度堆积并形成泡沫细胞是动脉粥样硬化的一个典型病理特征。
目的以THP-1(人急性单核细胞性白血病细胞株)为研究对象,体外观察肺炎衣原体(C.pn)感染对THP-1源性泡沫细胞形成的影响。
方法C.pn在人喉上皮癌(Hep-2)细胞内增殖。THP-1单核细胞给予160 nmol /L佛波酯(PMA)孵育48 h,诱导分化为巨噬细胞后随机分为4组:①阴性对照组:给予含50μg/ml低密度脂蛋白(LDL)的培养基孵育48 h;②阳性对照组:给予含50μg/ ml氧化型低密度脂蛋白(ox-LDL)的培养基孵育48 h;③C.pn感染浓度组:在负荷50μg / ml LDL的条件下,分别给予1×10~5、4×10~5、5×10~5、1×10~6 IFU C.pn感染48 h;④C.pn感染时间组:在负荷50μg / ml LDL的条件下,给予1×10~6IFU C.pn感染0、24、48、72 h。透射电镜和聚合酶链反应(PCR)鉴定C.pn有无感染Hep-2和THP-1源性巨噬细胞。运用油红O染色光镜下观察细胞浆内脂滴的变化,采用酶比色法分别检测细胞内总胆固醇(TC)和胆固醇酯(CE)含量的变化。
结果与阴性对照组比较,阳性对照组细胞内的脂滴明显增多,CE /TC比值明显增加(>50%) (p <0.05)。随着C.pn感染浓度的增加和时间的延长,细胞内的脂滴、CE和TC含量逐渐增多。与阴性对照组相比,高浓度的C.pn (5×10~5和1×10~6IFU)感染组的细胞内脂滴显著增多,CE /TC的比值分别有明显增加(>50%) (p < 0.05)。但CE/TC比值在C.pn感染72 h (68.6)和48 h (66.4%)时,差异无统计学意义(p>0.05)。与阳性对照组比较,1×10~6 IFU C.pn感染组细胞内的脂滴数量、CE /TC比值无统计学差异(p>0.05)。
结论在负荷LDL的条件下,高浓度的C.pn (5×10~5和1×10~6IFU)感染诱导THP-1源性泡沫细胞形成。
第二部分肺炎衣原体感染对参与巨噬细胞胆固醇代谢关键基因表达的影响
背景胆固醇代谢稳态的失衡贯穿于泡沫细胞形成的整个过程。
目的观察参与细胞内胆固醇代谢关键基因-清道夫受体A (SR-A1)、B (CD36)、血凝素样氧化低密度脂蛋白受体1(LOX-1)、酰基辅酶A:胆固醇酰基转移酶1(ACAT1)、ATP结合盒转运体A1 (ABCA1)和G1 (ABCG1)在肺炎衣原体(C.pn)诱导泡沫细胞形成中的作用。
方法THP-1单核细胞给予160 nmol/LPMA孵育48 h,诱导分化为巨噬细胞后随机分为4组:①对照组:给予含50μg/ml低密度脂蛋白(LDL)的培养基孵育48 h;②C.pn感染浓度组:在负荷LDL(50μg/ml)的条件下,分别给予1×10~5、4×10~5、5×10~5、1×10~6 IFU C.pn感染48 h;③C.pn感染时间组:在负荷LDL (50μg / ml)的条件下,给予1×10~6IFU C.pn感染0、24、48、72 h。④抗CD36单克隆抗体+ C.pn感染组:分别给予1:100、1:200、1:400的鼠抗人CD36单克隆抗体预孵1h,再给予含50μg/mlLDL和1×10~6 IFU C.pn感染48 h。分别运用RT-PCR和Western-blot检测①～③组SR-A1、CD36、LOX-1、ACAT1、ABCA1、ABCG1 mRNA和蛋白表达。运用油红O染色光镜下观察细胞浆内脂滴的变化,采用酶比色法分别检测细胞内总胆固醇(TC)和胆固醇酯(CE)含量的变化。
结果随着C.pn感染浓度的增加和时间的延长,SR-A1、ACAT1 mRNA和蛋白表达不仅逐渐上调,而且ABCA1、ABCG1 mRNA和蛋白表达也逐渐下降(所有p<0.05)。然而,C.pn感染不影响LOX-1 mRNA和蛋白表达(p>0.05)。与对照组比较,高浓度的C.pn感染组(1×10~6 IFU)的CD36 mRNA和蛋白表达有明显降低(p< 0.05)。从形态学和生化学的角度观察,给予不同滴度的鼠抗人CD36单克隆抗体干预后,C.pn (1×10~6IFU)感染诱导的泡沫细胞形成无显著变化。
结论C.pn感染负荷LDL的THP-1源性巨噬细胞后,通过增加SR-A1和ACAT1表达,抑制CD36、ABCA1和ABCG1表达,破坏巨噬细胞内胆固醇代谢的稳态,进而诱导泡沫细胞形成。
第三部分过氧化物酶体增殖物活化受体通路在肺炎衣原体诱导泡沫细胞形成中的作用
背景过氧化物酶体增殖物活化受体(PPARs)是调控巨噬细胞胆固醇代谢的关键核受体。
目的以THP-1源性巨噬细胞为研究对象,体外观察过氧化物酶体增殖物活化受体α(PPARα)、γ(PPARγ)在肺炎衣原体(C.pn)感染调控的关键基因(SR-A1、CD36、ACAT1、ABCA1、ABCG1)和泡沫细胞形成中的作用。
方法THP-1单核细胞给予160 nmol/LPMA孵育48 h,诱导分化为巨噬细胞后随机分为7组,①对照组:给予含50μg/ml低密度脂蛋白(LDL )的培养基孵育48 h;②C.pn感染浓度组:在负荷50μg / ml LDL的条件下,分别给予1×10~5、4×10~5、5×10~5、1×10~6 IFU C.pn感染48 h;③C.pn感染时间组:在负荷50μg / ml LDL的条件下,给予1×10~6 IFU C.pn感染0、24、48、72 h;④PPARα激动剂非诺贝特+C.pn感染组:分别给予含10、20、50μmol /L非诺贝特的培养基预孵2h后,再给予含50μg / ml LDL和1×10~6 IFU C.pn感染48 h;⑤非诺贝特组:给予含50μmol /L非诺贝特的培养基孵育48 h;⑥PPARγ配体罗格列酮+C.pn感染组:分别给予含1、10、20μmol /L罗格列酮的培养基预孵2h后,再给予含50μg / ml LDL和1×10~6 IFU C.pn感染48 h;⑦罗格列酮组:给予含20μmol /L罗格列酮的培养基孵育48 h。分别运用RT-PCR和Western-blot检测各组PPARα、PPARγ、SR-A1、CD36、ACAT1、ABCA1、ABCG1mRNA和蛋白表达。运用油红O染色观察细胞浆内脂滴的变化,酶比色法检测各组细胞内总胆固醇和胆固醇酯含量的变化。
结果C.pn感染呈浓度和时间依赖性地下调PPARα、PPARγmRNA和蛋白表达(p< 0.05)。与C.pn感染组比较,非诺贝特和罗格列酮不仅浓度依赖性地抑制C.pn感染诱导的SR-A1、ACAT1 mRNA和蛋白表达的增加(p < 0.05),而且浓度依赖性地抑制C.pn对ABCA1、ABCG1mRNA和蛋白表达的下调效应(p< 0.05)。与C.pn感染组比较,20μmol /L的罗格列酮可以逆转C.pn感染诱导的CD36 mRNA和蛋白表达的下调(p <0.05)。此外,从形态学和生化学的角度观察,高浓度的非诺贝特(20和50μmol /L)和罗格列酮(10和20μmol /L)明显抑制C.pn诱导的THP-1源性泡沫细胞形成。
结论C.pn部分通过PPARα和PPARγ途径,上调SR-A1、ACAT1表达,下调CD36、ABCA1、ABCG1表达,诱导THP-1源性泡沫细胞形成,这可能为进一步阐明C.pn感染促进动脉粥样硬化发生发展提供新的理论依据。
PartⅠEffect of Chlamydia pneumoniae infection on the formation ofTHP-1-derived foam Cells
Background A typical pathological hallmark of atherosclerosis is the excessiveaccumulation of cholesteryl esters in macrophages,leading to their conversion to foam cells.
Objective To observe the effect of Chlamydia pneumoniae (C.pn) infection on theformation of THP-1-derived foam cells in vitro.
Methods C.pn was propagated in Hep-2 cells.Human monocytic cell line (THP-1)were induced into macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h,and then were randomly allocated into four groups:①negative control group,RPMI 1640medium containing 50μg / ml low density lipoprotein (LDL) for 48 h;②positive controlgroup,RPMI 1640 medium containing 50μg / ml oxidized low density lipoprotein (ox-LDL)for 48 h;③different concentrations of C.pn infection group,50μg / ml LDL plus 1×10~5,4×10~5,5×10~5 and 1×10~6 IFU C.pn infection for 48 h;④different time of C.pn infectiongroup,50μg / ml LDL plus 1×10~6 IFU C.pn infection for 0,24,48 and 72 h.The infection ofC.pn on Hep-2 and THP-1 macrophages were assessed by transmission electron microscopeand polymerase chain reaction (PCR).Lipid droplets in cytoplasm were observed by oil red Ostaining.The contents of intracellular total cholesterol (TC) and cholesteryl esters (CE) weredetected by enzymic chromatometry.
Results Compared with negative control,there were significantly increases in theaccumulation of lipid droplets and the ratio of CE to TC (more than 50 percent) in positivecontrol (p＜0.05).C.pn infection increased the contents of intracellular lipid droplets,TC andCE in concentration-dependent and time-dependent manner.Higher concentrations of C.pninfection (5×10~5 and 1×10~6 IFU) group also obviously increased the accumulation of lipiddroplets and the ratio of CE to TC (more than 50 percent) compared with negative control (p＜0.05).However,the ratio of CE to TC in C.pn infection 72 h group (68.6 %) and 48 h group(66.4 % ) had no difference (p＞0.05).Compared with positive control,there was nodifferences in the number of lipid droplets and the ratio of CE to TC in C.pn infection (1×10~6IFU) group (p＞0.05).
Conclusion In the presence of LDL,higher concentrations of C.pn infection (5×10~5 and1×10~6 IFU) induce the formation of THP-1-derived foam cells.
PartⅡEffect of Chlamydia pneumoniae infection on the expressionsof key genes involved in macrophage cholesterol metabolism
Background The imbalance of cholesterol metabolism homeostasis in macrophagecontributes to foam cell formation.
Objective To investigate the roles of scavenger receptor A1 (SR-A1),B (CD36),lectin-like oxidized low density lipoprotein receptor-1(LOX-1),acyl-coenzyme A:cholesterolacyltransferase 1 (ACAT1),ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1)in Chlamydia pneumoniae (C.pn)-induced foam cell formation.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for48 h,and then were randomly allocated into four groups:①control group,RPMI 1640medium containing 50μg / ml low density lipoprotein (LDL) for 48 h;②differentconcentrations of C.pn infection group,50μg / ml LDL plus 1×10~5,4×10~5,5×10~5 and 1×10~6IFU C.pn infection for 48 h;③different time of C.pn infection group,50μg / ml LDL plus 1×10~6 IFU C.pn infection for 0,24,48 and 72 h;④mouse anti-human CD36 monoclonalantibody plus C.pn infection group,pre-treatment with different dilutions of mouseanti-human CD36 monoclonal antibody (1:100,1:200,1:400) for 1 h,50μg / ml LDL plus1×10~6 IFU C.pn infection for 48 h.The mRNA and protein expressions of SR-A1,CD36,LOX-1,ACAT1,ABCA1 and ABCG1 from group①to group③were determined byRT-PCR and Western-blot,respectively.Intracellular lipid droplets were observed by oil red Ostaining.The contents of intracellular total cholesterol (TC) and cholesteryl esters (CE) weredetected by enzymic chromatometry.
Results C.pn infection not only up-regulated the mRNA and protein expressions ofSR-A1 and ACAT1,but also down-regulated the mRNA and protein expressions of ABCA1and ABCG1 in concentration-dependent and time-dependent manner in LDL-treated THP-1macrophages (all p＜0.05).However,C.pn infection had no effect on the expression ofLOX-1 at mRNA and protein levels compared with control group (p＞0.05).Compared withcontrol group,the down-regulation of CD36 at mRNA and protein expressions was observedin high concentration of C.pn infection (1×10~6 IFU) group.In addition,from morphologicaland biochemical criteria,C.pn-induced foam cell formation derived from THP-1 had not beeninfluenced after pre-treatment with different dilutions of mouse anti-human CD36 monoclonalantibody.
Conclusion C.pn infection may destroy the homeostasis of intracellular cholesterolmetabolism by increasing SR-A1 and ACAT1 expressions,and inhibiting CD36,ABCA1 andABCG1 expressions in LDL-treated THP-1-derived macrophages,which leads to foam cellformation.
PartⅢThe roles of peroxisome proliferator-activated receptorspathways in Chlamydia pneumoniae-induced foam cell formation
Background peroxisome proliferator-activated receptors (PPARs) are key nuclearreceptors that regulate macrophage cholesterol metabolism.
Objective To investigate the effects of peroxisome proliferator-activated receptorα(PPARα) andγ(PPARγ) on the expressions of SR-A1,CD36,ACAT1,ABCA1 andABCG1 regulated by Chlamydia pneumoniae (C.pn) infection,and to discuss the pathways ofC.pn-induced foam cell formation.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for48 h.and then were randomly allocated into seven groups:①control group,RPMI 1640medium containing 50μg / ml low density lipoprotein (LDL) for 48 h;②differentconcentrations of C.pn infection group,50μg / ml LDL plus 1×10~5,4×10~5,5×10~5 and 1×10~6IFU C.pn infection for 48 h;③different time of C.pn infection group,50μg / ml LDL plus1×10~6 IFU C.pn infection for 0,24,48 and 72 h;④Fenofibrate (a specific PPARαagonist)plus C.pn infection group,pretreatment with different concentrations of fenofibrate (10、20、50μmol/L) for 2 h,50μg / ml LDL plus 1×10~6 IFU C.pn infection for 48 h;⑤Fenofibrategroup,RPMI 1640 medium containing 50μmol/L fenofibrate for 48 h;⑥Rosiglitazone (aspecific PPARγligand) plus C.pn infection group,pretreatment with different concentrationsof rosiglitazone (1、10、20μmol/L) for 2 h,50μg / ml LDL plus 1×10~6 IFU C.pn infection for48 h;⑦Rosiglitazone group,RPMI 1640 medium containing 20μmol/L rosiglitazone for48 h.The mRNA and protein expressions of PPARα,PPARγ,SR-A1,ACAT1,ABCA1 andABCG1 were determined by RT-PCR and Western-blot,respectively.Lipid droplets incytoplasm were observed by oil red O staining.The contents of intracellular cholesteryl esterswere detected by enzymic chromatometry.
Results C.pn infection suppressed the expressions of PPARαand PPARγat mRNAand protein levels in concentration-dependent and time-dependent manner in LDL-treatedTHP-1 macrophages (all p＜0.05).Compared with C.pn infection group,not only the up-regulation of SR-A1 and ACAT1 but also the down-regulation of ABCA1 and ABCG1 atmRNA and protein levels by C.pn infection were concentration-dependently inhibited byfenofibrate and rosiglitazone (all p＜0.05).Compared with C.pn infection group,20μmol/Lrosiglitazone reversed the down-regulation of CD36 by C.pn infection (p＜0.05).In addition,from morphological and biochemical criteria,higher concentrations of fenofibrate (20 and 50μmol/L) and rosiglitazone (10 and 20μmol/L) markedly inhibited THP-1-derived foam cellformation induced by C.pn infection.
Conclusion C.pn infection induces THP-1-derived foam cell formation byup-regulating SR-A1 and ACAT1 expressions and down-regulating CD36,ABCA1 andABCG1 expressions partly via PPARαand PPARγ-dependent pathways,which mayprovide new insights for the development and progression of atherosclerosis initiated by C.pninfection.
背景胆固醇酯在巨噬细胞内过度堆积并形成泡沫细胞是动脉粥样硬化的一个典型病理特征。
目的以THP-1(人急性单核细胞性白血病细胞株)为研究对象,体外观察肺炎衣原体(C.pn)感染对THP-1源性泡沫细胞形成的影响。
方法C.pn在人喉上皮癌(Hep-2)细胞内增殖。THP-1单核细胞给予160 nmol /L佛波酯(PMA)孵育48 h,诱导分化为巨噬细胞后随机分为4组:①阴性对照组:给予含50μg/ml低密度脂蛋白(LDL)的培养基孵育48 h;②阳性对照组:给予含50μg/ ml氧化型低密度脂蛋白(ox-LDL)的培养基孵育48 h;③C.pn感染浓度组:在负荷50μg / ml LDL的条件下,分别给予1×10~5、4×10~5、5×10~5、1×10~6 IFU C.pn感染48 h;④C.pn感染时间组:在负荷50μg / ml LDL的条件下,给予1×10~6IFU C.pn感染0、24、48、72 h。透射电镜和聚合酶链反应(PCR)鉴定C.pn有无感染Hep-2和THP-1源性巨噬细胞。运用油红O染色光镜下观察细胞浆内脂滴的变化,采用酶比色法分别检测细胞内总胆固醇(TC)和胆固醇酯(CE)含量的变化。
结果与阴性对照组比较,阳性对照组细胞内的脂滴明显增多,CE /TC比值明显增加(>50%) (p <0.05)。随着C.pn感染浓度的增加和时间的延长,细胞内的脂滴、CE和TC含量逐渐增多。与阴性对照组相比,高浓度的C.pn (5×10~5和1×10~6IFU)感染组的细胞内脂滴显著增多,CE /TC的比值分别有明显增加(>50%) (p < 0.05)。但CE/TC比值在C.pn感染72 h (68.6)和48 h (66.4%)时,差异无统计学意义(p>0.05)。与阳性对照组比较,1×10~6 IFU C.pn感染组细胞内的脂滴数量、CE /TC比值无统计学差异(p>0.05)。
结论在负荷LDL的条件下,高浓度的C.pn (5×10~5和1×10~6IFU)感染诱导THP-1源性泡沫细胞形成。
第二部分肺炎衣原体感染对参与巨噬细胞胆固醇代谢关键基因表达的影响
背景胆固醇代谢稳态的失衡贯穿于泡沫细胞形成的整个过程。
目的观察参与细胞内胆固醇代谢关键基因-清道夫受体A (SR-A1)、B (CD36)、血凝素样氧化低密度脂蛋白受体1(LOX-1)、酰基辅酶A:胆固醇酰基转移酶1(ACAT1)、ATP结合盒转运体A1 (ABCA1)和G1 (ABCG1)在肺炎衣原体(C.pn)诱导泡沫细胞形成中的作用。
方法THP-1单核细胞给予160 nmol/LPMA孵育48 h,诱导分化为巨噬细胞后随机分为4组:①对照组:给予含50μg/ml低密度脂蛋白(LDL)的培养基孵育48 h;②C.pn感染浓度组:在负荷LDL(50μg/ml)的条件下,分别给予1×10~5、4×10~5、5×10~5、1×10~6 IFU C.pn感染48 h;③C.pn感染时间组:在负荷LDL (50μg / ml)的条件下,给予1×10~6IFU C.pn感染0、24、48、72 h。④抗CD36单克隆抗体+ C.pn感染组:分别给予1:100、1:200、1:400的鼠抗人CD36单克隆抗体预孵1h,再给予含50μg/mlLDL和1×10~6 IFU C.pn感染48 h。分别运用RT-PCR和Western-blot检测①～③组SR-A1、CD36、LOX-1、ACAT1、ABCA1、ABCG1 mRNA和蛋白表达。运用油红O染色光镜下观察细胞浆内脂滴的变化,采用酶比色法分别检测细胞内总胆固醇(TC)和胆固醇酯(CE)含量的变化。
结果随着C.pn感染浓度的增加和时间的延长,SR-A1、ACAT1 mRNA和蛋白表达不仅逐渐上调,而且ABCA1、ABCG1 mRNA和蛋白表达也逐渐下降(所有p<0.05)。然而,C.pn感染不影响LOX-1 mRNA和蛋白表达(p>0.05)。与对照组比较,高浓度的C.pn感染组(1×10~6 IFU)的CD36 mRNA和蛋白表达有明显降低(p< 0.05)。从形态学和生化学的角度观察,给予不同滴度的鼠抗人CD36单克隆抗体干预后,C.pn (1×10~6IFU)感染诱导的泡沫细胞形成无显著变化。
结论C.pn感染负荷LDL的THP-1源性巨噬细胞后,通过增加SR-A1和ACAT1表达,抑制CD36、ABCA1和ABCG1表达,破坏巨噬细胞内胆固醇代谢的稳态,进而诱导泡沫细胞形成。
第三部分过氧化物酶体增殖物活化受体通路在肺炎衣原体诱导泡沫细胞形成中的作用
背景过氧化物酶体增殖物活化受体(PPARs)是调控巨噬细胞胆固醇代谢的关键核受体。
目的以THP-1源性巨噬细胞为研究对象,体外观察过氧化物酶体增殖物活化受体α(PPARα)、γ(PPARγ)在肺炎衣原体(C.pn)感染调控的关键基因(SR-A1、CD36、ACAT1、ABCA1、ABCG1)和泡沫细胞形成中的作用。
方法THP-1单核细胞给予160 nmol/LPMA孵育48 h,诱导分化为巨噬细胞后随机分为7组,①对照组:给予含50μg/ml低密度脂蛋白(LDL )的培养基孵育48 h;②C.pn感染浓度组:在负荷50μg / ml LDL的条件下,分别给予1×10~5、4×10~5、5×10~5、1×10~6 IFU C.pn感染48 h;③C.pn感染时间组:在负荷50μg / ml LDL的条件下,给予1×10~6 IFU C.pn感染0、24、48、72 h;④PPARα激动剂非诺贝特+C.pn感染组:分别给予含10、20、50μmol /L非诺贝特的培养基预孵2h后,再给予含50μg / ml LDL和1×10~6 IFU C.pn感染48 h;⑤非诺贝特组:给予含50μmol /L非诺贝特的培养基孵育48 h;⑥PPARγ配体罗格列酮+C.pn感染组:分别给予含1、10、20μmol /L罗格列酮的培养基预孵2h后,再给予含50μg / ml LDL和1×10~6 IFU C.pn感染48 h;⑦罗格列酮组:给予含20μmol /L罗格列酮的培养基孵育48 h。分别运用RT-PCR和Western-blot检测各组PPARα、PPARγ、SR-A1、CD36、ACAT1、ABCA1、ABCG1mRNA和蛋白表达。运用油红O染色观察细胞浆内脂滴的变化,酶比色法检测各组细胞内总胆固醇和胆固醇酯含量的变化。
结果C.pn感染呈浓度和时间依赖性地下调PPARα、PPARγmRNA和蛋白表达(p< 0.05)。与C.pn感染组比较,非诺贝特和罗格列酮不仅浓度依赖性地抑制C.pn感染诱导的SR-A1、ACAT1 mRNA和蛋白表达的增加(p < 0.05),而且浓度依赖性地抑制C.pn对ABCA1、ABCG1mRNA和蛋白表达的下调效应(p< 0.05)。与C.pn感染组比较,20μmol /L的罗格列酮可以逆转C.pn感染诱导的CD36 mRNA和蛋白表达的下调(p <0.05)。此外,从形态学和生化学的角度观察,高浓度的非诺贝特(20和50μmol /L)和罗格列酮(10和20μmol /L)明显抑制C.pn诱导的THP-1源性泡沫细胞形成。
结论C.pn部分通过PPARα和PPARγ途径,上调SR-A1、ACAT1表达,下调CD36、ABCA1、ABCG1表达,诱导THP-1源性泡沫细胞形成,这可能为进一步阐明C.pn感染促进动脉粥样硬化发生发展提供新的理论依据。
PartⅠEffect of Chlamydia pneumoniae infection on the formation ofTHP-1-derived foam Cells
Background A typical pathological hallmark of atherosclerosis is the excessiveaccumulation of cholesteryl esters in macrophages,leading to their conversion to foam cells.
Objective To observe the effect of Chlamydia pneumoniae (C.pn) infection on theformation of THP-1-derived foam cells in vitro.
Methods C.pn was propagated in Hep-2 cells.Human monocytic cell line (THP-1)were induced into macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h,and then were randomly allocated into four groups:①negative control group,RPMI 1640medium containing 50μg / ml low density lipoprotein (LDL) for 48 h;②positive controlgroup,RPMI 1640 medium containing 50μg / ml oxidized low density lipoprotein (ox-LDL)for 48 h;③different concentrations of C.pn infection group,50μg / ml LDL plus 1×10~5,4×10~5,5×10~5 and 1×10~6 IFU C.pn infection for 48 h;④different time of C.pn infectiongroup,50μg / ml LDL plus 1×10~6 IFU C.pn infection for 0,24,48 and 72 h.The infection ofC.pn on Hep-2 and THP-1 macrophages were assessed by transmission electron microscopeand polymerase chain reaction (PCR).Lipid droplets in cytoplasm were observed by oil red Ostaining.The contents of intracellular total cholesterol (TC) and cholesteryl esters (CE) weredetected by enzymic chromatometry.
Results Compared with negative control,there were significantly increases in theaccumulation of lipid droplets and the ratio of CE to TC (more than 50 percent) in positivecontrol (p＜0.05).C.pn infection increased the contents of intracellular lipid droplets,TC andCE in concentration-dependent and time-dependent manner.Higher concentrations of C.pninfection (5×10~5 and 1×10~6 IFU) group also obviously increased the accumulation of lipiddroplets and the ratio of CE to TC (more than 50 percent) compared with negative control (p＜0.05).However,the ratio of CE to TC in C.pn infection 72 h group (68.6 %) and 48 h group(66.4 % ) had no difference (p＞0.05).Compared with positive control,there was nodifferences in the number of lipid droplets and the ratio of CE to TC in C.pn infection (1×10~6IFU) group (p＞0.05).
Conclusion In the presence of LDL,higher concentrations of C.pn infection (5×10~5 and1×10~6 IFU) induce the formation of THP-1-derived foam cells.
PartⅡEffect of Chlamydia pneumoniae infection on the expressionsof key genes involved in macrophage cholesterol metabolism
Background The imbalance of cholesterol metabolism homeostasis in macrophagecontributes to foam cell formation.
Objective To investigate the roles of scavenger receptor A1 (SR-A1),B (CD36),lectin-like oxidized low density lipoprotein receptor-1(LOX-1),acyl-coenzyme A:cholesterolacyltransferase 1 (ACAT1),ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1)in Chlamydia pneumoniae (C.pn)-induced foam cell formation.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for48 h,and then were randomly allocated into four groups:①control group,RPMI 1640medium containing 50μg / ml low density lipoprotein (LDL) for 48 h;②differentconcentrations of C.pn infection group,50μg / ml LDL plus 1×10~5,4×10~5,5×10~5 and 1×10~6IFU C.pn infection for 48 h;③different time of C.pn infection group,50μg / ml LDL plus 1×10~6 IFU C.pn infection for 0,24,48 and 72 h;④mouse anti-human CD36 monoclonalantibody plus C.pn infection group,pre-treatment with different dilutions of mouseanti-human CD36 monoclonal antibody (1:100,1:200,1:400) for 1 h,50μg / ml LDL plus1×10~6 IFU C.pn infection for 48 h.The mRNA and protein expressions of SR-A1,CD36,LOX-1,ACAT1,ABCA1 and ABCG1 from group①to group③were determined byRT-PCR and Western-blot,respectively.Intracellular lipid droplets were observed by oil red Ostaining.The contents of intracellular total cholesterol (TC) and cholesteryl esters (CE) weredetected by enzymic chromatometry.
Results C.pn infection not only up-regulated the mRNA and protein expressions ofSR-A1 and ACAT1,but also down-regulated the mRNA and protein expressions of ABCA1and ABCG1 in concentration-dependent and time-dependent manner in LDL-treated THP-1macrophages (all p＜0.05).However,C.pn infection had no effect on the expression ofLOX-1 at mRNA and protein levels compared with control group (p＞0.05).Compared withcontrol group,the down-regulation of CD36 at mRNA and protein expressions was observedin high concentration of C.pn infection (1×10~6 IFU) group.In addition,from morphologicaland biochemical criteria,C.pn-induced foam cell formation derived from THP-1 had not beeninfluenced after pre-treatment with different dilutions of mouse anti-human CD36 monoclonalantibody.
Conclusion C.pn infection may destroy the homeostasis of intracellular cholesterolmetabolism by increasing SR-A1 and ACAT1 expressions,and inhibiting CD36,ABCA1 andABCG1 expressions in LDL-treated THP-1-derived macrophages,which leads to foam cellformation.
PartⅢThe roles of peroxisome proliferator-activated receptorspathways in Chlamydia pneumoniae-induced foam cell formation
Background peroxisome proliferator-activated receptors (PPARs) are key nuclearreceptors that regulate macrophage cholesterol metabolism.
Objective To investigate the effects of peroxisome proliferator-activated receptorα(PPARα) andγ(PPARγ) on the expressions of SR-A1,CD36,ACAT1,ABCA1 andABCG1 regulated by Chlamydia pneumoniae (C.pn) infection,and to discuss the pathways ofC.pn-induced foam cell formation.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for48 h.and then were randomly allocated into seven groups:①control group,RPMI 1640medium containing 50μg / ml low density lipoprotein (LDL) for 48 h;②differentconcentrations of C.pn infection group,50μg / ml LDL plus 1×10~5,4×10~5,5×10~5 and 1×10~6IFU C.pn infection for 48 h;③different time of C.pn infection group,50μg / ml LDL plus1×10~6 IFU C.pn infection for 0,24,48 and 72 h;④Fenofibrate (a specific PPARαagonist)plus C.pn infection group,pretreatment with different concentrations of fenofibrate (10、20、50μmol/L) for 2 h,50μg / ml LDL plus 1×10~6 IFU C.pn infection for 48 h;⑤Fenofibrategroup,RPMI 1640 medium containing 50μmol/L fenofibrate for 48 h;⑥Rosiglitazone (aspecific PPARγligand) plus C.pn infection group,pretreatment with different concentrationsof rosiglitazone (1、10、20μmol/L) for 2 h,50μg / ml LDL plus 1×10~6 IFU C.pn infection for48 h;⑦Rosiglitazone group,RPMI 1640 medium containing 20μmol/L rosiglitazone for48 h.The mRNA and protein expressions of PPARα,PPARγ,SR-A1,ACAT1,ABCA1 andABCG1 were determined by RT-PCR and Western-blot,respectively.Lipid droplets incytoplasm were observed by oil red O staining.The contents of intracellular cholesteryl esterswere detected by enzymic chromatometry.
Results C.pn infection suppressed the expressions of PPARαand PPARγat mRNAand protein levels in concentration-dependent and time-dependent manner in LDL-treatedTHP-1 macrophages (all p＜0.05).Compared with C.pn infection group,not only the up-regulation of SR-A1 and ACAT1 but also the down-regulation of ABCA1 and ABCG1 atmRNA and protein levels by C.pn infection were concentration-dependently inhibited byfenofibrate and rosiglitazone (all p＜0.05).Compared with C.pn infection group,20μmol/Lrosiglitazone reversed the down-regulation of CD36 by C.pn infection (p＜0.05).In addition,from morphological and biochemical criteria,higher concentrations of fenofibrate (20 and 50μmol/L) and rosiglitazone (10 and 20μmol/L) markedly inhibited THP-1-derived foam cellformation induced by C.pn infection.
Conclusion C.pn infection induces THP-1-derived foam cell formation byup-regulating SR-A1 and ACAT1 expressions and down-regulating CD36,ABCA1 andABCG1 expressions partly via PPARαand PPARγ-dependent pathways,which mayprovide new insights for the development and progression of atherosclerosis initiated by C.pninfection.
引文
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