肺炎衣原体诱导THP-1源性巨噬细胞胆固醇代谢稳态失衡的信号机制研究
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摘要
第一部分肺炎衣原体对THP-1源性巨噬细胞胆固醇代谢的影响
目的观察肺炎衣原体(C.pn)对人单核细胞株(THP-1)源性巨噬细胞内胆固醇含量及参与胆固醇代谢的关键基因,包括清道夫受体A1 (SR-A1)、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ATP结合盒转运体G1 (ABCG1)表达的影响。
方法在宿主细胞人喉上皮癌(Hep-2)细胞内繁殖C.pn。以160nmol/L佛波酯(PMA)诱导THP-1细胞48h后,分化为巨噬细胞。随机分为5组：(1)对照组；(2)1×105IFU C.pn感染组；(3)4×105IFU C.pn感染组；(4)5×105IFU Cpn感染组；(5)1×106IFU C.pn感染组。以上各组均在50μg/ml LDL存在条件下,孵育48h。采用透射电镜法鉴定C.pn对THP-1源性巨噬细胞的感染。运用酶化学法检测细胞内总胆固醇(TC)和胆固醇酯(CE)含量,油红0染色观察细胞浆内脂滴含量及进行泡沫细胞计数,分别使用RT-PCR和Western-blot的方法检测各组细胞SR-A1、ACAT1、ABCA1/G1基因和蛋白表达。
结果随着C.pn感染浓度的递增,细胞内的脂质含量、泡沫细胞数逐渐增加,TC和CE含量也逐渐增多,SR-A1、ACAT1基因和蛋白表达逐渐上调,而且ABCA1/G1基因和蛋白表达也逐渐下调。
结论C.pn感染THP-1源性巨噬细胞后,通过上调SR-A1和ACAT1表达,下调ABCA1/G1表达,增加胆固醇摄入和胆固醇酯合成,减少胆固醇流出,诱导巨噬细胞内的胆固醇代谢稳态失衡。
第二部分过氧化物酶体增殖物活化受体γ信号通路在肺炎衣原体诱导巨噬细胞胆固醇代谢稳态失衡中的作用
目的观察PPARγ信号通路在C.pn调控巨噬细胞内胆固醇代谢关键基因SR-A1、ACAT1、ABCA1/G1表达中的作用。
方法以160 nmol/L PMA诱导THP-1细胞48 h后,分化为巨噬细胞。随机分为4组：(1)阴性对照组；(2)阳性对照组：给予1×106IFU C.pn感染；(3)罗格列酮(PPARγ特异性激动剂)干预组：分别给予1、10、20μmol/L罗格列酮预孵2 h后,再给予1×106 IFU C.pn感染；(4)单纯罗格列酮组：单纯给予20μmol/L罗格列酮预孵2h。以上各组均在负荷50μg/ml LDL的条件下,孵育48h。运用油红O染色观察各组细胞胞浆内脂滴含量和泡沫细胞计数的变化。采用酶化学法检测各组细胞TC和CE含量的变化,分别运用RT-PCR和Western-blot的方法检测各组细胞PPARγ、ACAT1、SR-A1、ABCA1/G1基因和蛋白表达。
结果随着C.pn感染浓度的递增,PPARγ基因和蛋白的表达逐渐下调。与阳性对照组相比,罗格列酮干预后不仅呈浓度依赖性地抑制C.pn诱导的SR-A1、ACAT1基因和蛋白表达上调,而且呈浓度依赖性地抑制C.pn诱导的ABCA1/G1基因和蛋白表达下调。提示PPAR y参与了C.pn通过调控细胞内胆固醇代谢关键基因SR-A1、ACAT1、ABCA1/G1的表达,从而破坏胆固醇代谢稳态的过程。
结论C.pn感染部分通过PPARγ信号通路,上调ACAT1、SR-A1表达,下调ABCA1/G1表达,增加胆固醇摄入和胆固醇酯合成,减少胆固醇流出,从而诱导THP-1源性巨噬细胞胆固醇代谢稳态的失衡。
第三部分c-Jun氨基末端激酶信号通路在肺炎衣原体诱导巨噬细胞胆固醇代谢稳态失衡中的作用
目的观察c-Jun氨基末端激酶(JNK)在C.pn通过PPARγ信号通路调控巨噬细胞内胆固醇代谢关键基因SR-A1、ACAT1、ABCA1/G1表达中的作用。方法以160nmol/L佛波酯(PMA)诱导THP-1细胞48h后,分化为巨噬细胞。随机分为4组,(1)阴性对照组；(2)阳性对照组：给予1×106IFU C.pn感染；(3)JNK抑制剂SP600125干预组：分别给予1、10、20μmol/L的SP600125预孵2h后,再给予1×106IFU C.pn感染；(4)单纯SP600125组：单纯给予20μmol／L SP600125预孵2h。以上各组均在负荷50μg/ml LDL的条件下,孵育48h。运用酶化学法检测各组细胞内TC和CE含量的变化,采用油红O染色观察细胞胞浆内脂滴含量的变化和泡沫细胞计数。分别使用RT-PCR和Western-blot的方法检测各组PPARγ、ACAT1、SR-A1、ABCA1/G1基因和蛋白表达。
结果与阳性对照组相比,SP600125干预后不仅呈浓度依赖性地抑制C.pn感染对PPARy表达的下调,而且呈浓度依赖性地抑制C.pn感染调控的PPARy的下游靶基因SR-A1、ACAT1、ABCA1/G1的表达(p<0.05)。提示JNK参与了C.pn通过PPARy信号通路调控SR-A1、ACAT1、ABCA1/G1的表达,破坏胆固醇代谢稳态的过程。
结论C.pn部分通过JNK-PPARy信号通路,上调SR-A1、ACAT1基因和蛋白表达,下调ABCA1/G1基因和蛋白表达,增加胆固醇摄入和胆固醇酯合成,减少胆固醇流出,从而诱导THP-1源性巨噬细胞胆固醇代谢稳态的失衡。这可能为我们进一步探讨C.pn感染促进动脉粥样硬化的机制提供新的理论依据。
PartⅠEffects of Chlamydia pneumoniae infection on the Cholesterol Metabolism In THP-1-derived macrophages
Objective To observe the effects of Chlamydia pneumoniae (C.pn) infection on the cholesterol metabolism in THP-1-derived macrophages.
Methods C.pn strain AR-39 was propagated in HEp-2 cells by centrifugation-driven infection. The human THP-1 monocytic leukemia cell line differentiated to macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h, and then were randomly allocated into five groups:①control group;②-⑤different concentrations(1×105,4×105,5×105 and 1×106 IFU) of C.pn infection group; each group was incubated with 50μg/ml LDL for 48 h. The infection of C.pn on THP-1-derived macrophages was figured by transmission electron microscope. Lipid droplets in cytoplasm and the number of foam cells were observed by oil red O staining. The contents of intracellular total cholesterol (TC) and cholesteryl esters (CE) were measured by enzymic chromatometry. The mRNA and protein
expressions of scavenger receptor A1 (SR-A1), acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), ATP binding cassette transporter Al (ABCA1) and G1 (ABCG1) from each group were determined by RT-PCR and Western-blot, respectively.
Results Compared with control group, C.pn infection increased the contents of intracellular lipid droplets, the number of foam cells, TC and CE in a concentration-dependent manner. Moreover, C.pn infection not only up-regulated the mRNA and protein expressions of SR-A1 and ACAT1, but also down-regulated the mRNA and protein expressions of ABCA1 and ABCG1 in a concentration-dependent manner in LDL-treated THP-1 macrophages (all p<0.05). Higher concentrations of C.pn infection (5×105 and 1×106 IFU) group obviously cause the effects as mentioned above (p<0.05).
Conclusion C.pn infection may destroy the homeostasis of intracellular cholesterol metabolism by increasing SR-A1 and ACAT1 expressions, and inhibiting ABCA1 and ABCG1 expressions in LDL-treated THP-1-derived macrophages, which leads to foam cell formation.
Part II The role of peroxisome proliferator-activated receptor y pathway in Chlamydia pneumoniae-induced imbalance of cholesterol metabolism homeostasis
Objective To investigate the effects of peroxisome proliferator-activated receptor y (PPAR y) on the expressions of SR-A1, ACAT1, ABCA1 and ABCG1 regulated by Chlamydia pneumoniae (C.pn) infection, and to discuss the pathways of C.pn-induced imbalance of cholesterol metabolism homeostasis.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for 48 h. and then were randomly allocated into seven groups:①control group,50μg/ml low density lipoprotein (LDL) for 48 h;②C.pn infection group,50μg/ml LDL plus 1×106 IFU C.pn infection for 48 h;③Rosiglitazone (a specific PPARγligand) plus C.pn infection group, pretreatment with different concentrations of rosiglitazone (1、10、20μmol/L) for 2 h,50μg/ml LDL plus 1×106 IFU C.pn infection for 48 h;④Rosiglitazone group,20μmol/L rosiglitazone for 48 h. Lipid droplets in cytoplasm and the number of foam cells were observed by oil red O staining. The contents of intracellular cholesteryl esters were detected by enzymic chromatometry. The mRNA and protein expressions of PPARγ, SR-A1, ACAT1, ABCA1 and ABCG1 were determined by RT-PCR and Western-blot, respectively.
Results C.pn infection suppressed the expression of PPARγat mRNA and protein levels in concentration-dependent manner in LDL-treated THP-1 macrophages (all p <0.05). From morphological and biochemical criteria, higher concentrations of rosiglitazone (10 and 20μmol/L) markedly inhibited C.pn-induced imbalance of cholesterol metabolism homeostasis and foam cell formation. 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 at mRNA and protein levels by C.pn infection were concentration-dependently inhibited by rosiglitazone (all p<0.05).
Conclusion C.pn infection induces imbalance of cholesterol metabolism homeostasis and foam cell formation in THP-1 derived macrophages by up-regulating SR-A1 and ACAT1 expressions and down-regulating ABCA1 and ABCG1 expressions partly via PPAR y-dependent pathway.
PartⅢThe role of c-Jun NH2 terminal kinase pathway in Chlamydia pneumoniae-induced imbalance of cholesterol metabolism homeostasis
Objective To investigate the effects of c-Jun NH2 terminal kinase (JNK) on the expressions of SR-A1, ACAT1, ABCA1 and ABCG1 regulated by Chlamydia pneumoniae (C.pn) infection, and to discuss the pathways of C.pn-induced imbalance of cholesterol metabolism homeostasis.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for 48 h. and then were randomly allocated into seven groups:①control group,50μg/ml low density lipoprotein (LDL) for 48 h;②different concentrations of C.pn infection group,50μg/ml LDL plus 1×105,4×105,5×105 and 1×106 IFU C.pn infection for 48 h;③SP600125 (a specific JNK inhibitor) plus C.pn infection group, pretreatment with different concentrations of (1、10、20μmol/L) for 2 h,50μg/ml LDL plus 1×106 IFU C.pn infection for 48 h;④SP600125 group,20μmol /L SP600125 for 48 h. Lipid droplets in cytoplasm and the number of foam cells were observed by oil red O staining. The contents of intracellular cholesteryl esters were detected by enzymic chromatometry. The mRNA and protein expressions of PPARγ, SR-A1, ACAT1, ABCA1 and ABCG1 were determined by RT-PCR and Western-blot, respectively.
Results From morphological and biochemical criteria, higher concentrations of SP600125 (10 and 20μmol/L) markedly inhibited C.pn-induced imbalance of cholesterol metabolism homeostasis and foam cell formation. Compared with C.pn infection group, not only the down-regulation of PPAR y, but also the regulation of the taget genes of PPAR y (SR-A1, ACAT1, ABCA1 and ABCG1) at mRNA and protein levels by C.pn infection were concentration-dependently inhibited by SP600125(all p<0.05).
Conclusion C.pn infection induces imbalance of cholesterol metabolism homeostasis and foam cell formation in THP-1 derived macrophages by up-regulating SR-A1 and ACAT1 expressions and down-regulating ABCA1 and ABCG1 expressions partly via JNK-PPARγdependent pathway.
目的观察肺炎衣原体(C.pn)对人单核细胞株(THP-1)源性巨噬细胞内胆固醇含量及参与胆固醇代谢的关键基因,包括清道夫受体A1 (SR-A1)、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ATP结合盒转运体G1 (ABCG1)表达的影响。
方法在宿主细胞人喉上皮癌(Hep-2)细胞内繁殖C.pn。以160nmol/L佛波酯(PMA)诱导THP-1细胞48h后,分化为巨噬细胞。随机分为5组：(1)对照组；(2)1×105IFU C.pn感染组；(3)4×105IFU C.pn感染组；(4)5×105IFU Cpn感染组；(5)1×106IFU C.pn感染组。以上各组均在50μg/ml LDL存在条件下,孵育48h。采用透射电镜法鉴定C.pn对THP-1源性巨噬细胞的感染。运用酶化学法检测细胞内总胆固醇(TC)和胆固醇酯(CE)含量,油红0染色观察细胞浆内脂滴含量及进行泡沫细胞计数,分别使用RT-PCR和Western-blot的方法检测各组细胞SR-A1、ACAT1、ABCA1/G1基因和蛋白表达。
结果随着C.pn感染浓度的递增,细胞内的脂质含量、泡沫细胞数逐渐增加,TC和CE含量也逐渐增多,SR-A1、ACAT1基因和蛋白表达逐渐上调,而且ABCA1/G1基因和蛋白表达也逐渐下调。
结论C.pn感染THP-1源性巨噬细胞后,通过上调SR-A1和ACAT1表达,下调ABCA1/G1表达,增加胆固醇摄入和胆固醇酯合成,减少胆固醇流出,诱导巨噬细胞内的胆固醇代谢稳态失衡。
第二部分过氧化物酶体增殖物活化受体γ信号通路在肺炎衣原体诱导巨噬细胞胆固醇代谢稳态失衡中的作用
目的观察PPARγ信号通路在C.pn调控巨噬细胞内胆固醇代谢关键基因SR-A1、ACAT1、ABCA1/G1表达中的作用。
方法以160 nmol/L PMA诱导THP-1细胞48 h后,分化为巨噬细胞。随机分为4组：(1)阴性对照组；(2)阳性对照组：给予1×106IFU C.pn感染；(3)罗格列酮(PPARγ特异性激动剂)干预组：分别给予1、10、20μmol/L罗格列酮预孵2 h后,再给予1×106 IFU C.pn感染；(4)单纯罗格列酮组：单纯给予20μmol/L罗格列酮预孵2h。以上各组均在负荷50μg/ml LDL的条件下,孵育48h。运用油红O染色观察各组细胞胞浆内脂滴含量和泡沫细胞计数的变化。采用酶化学法检测各组细胞TC和CE含量的变化,分别运用RT-PCR和Western-blot的方法检测各组细胞PPARγ、ACAT1、SR-A1、ABCA1/G1基因和蛋白表达。
结果随着C.pn感染浓度的递增,PPARγ基因和蛋白的表达逐渐下调。与阳性对照组相比,罗格列酮干预后不仅呈浓度依赖性地抑制C.pn诱导的SR-A1、ACAT1基因和蛋白表达上调,而且呈浓度依赖性地抑制C.pn诱导的ABCA1/G1基因和蛋白表达下调。提示PPAR y参与了C.pn通过调控细胞内胆固醇代谢关键基因SR-A1、ACAT1、ABCA1/G1的表达,从而破坏胆固醇代谢稳态的过程。
结论C.pn感染部分通过PPARγ信号通路,上调ACAT1、SR-A1表达,下调ABCA1/G1表达,增加胆固醇摄入和胆固醇酯合成,减少胆固醇流出,从而诱导THP-1源性巨噬细胞胆固醇代谢稳态的失衡。
第三部分c-Jun氨基末端激酶信号通路在肺炎衣原体诱导巨噬细胞胆固醇代谢稳态失衡中的作用
目的观察c-Jun氨基末端激酶(JNK)在C.pn通过PPARγ信号通路调控巨噬细胞内胆固醇代谢关键基因SR-A1、ACAT1、ABCA1/G1表达中的作用。方法以160nmol/L佛波酯(PMA)诱导THP-1细胞48h后,分化为巨噬细胞。随机分为4组,(1)阴性对照组；(2)阳性对照组：给予1×106IFU C.pn感染；(3)JNK抑制剂SP600125干预组：分别给予1、10、20μmol/L的SP600125预孵2h后,再给予1×106IFU C.pn感染；(4)单纯SP600125组：单纯给予20μmol／L SP600125预孵2h。以上各组均在负荷50μg/ml LDL的条件下,孵育48h。运用酶化学法检测各组细胞内TC和CE含量的变化,采用油红O染色观察细胞胞浆内脂滴含量的变化和泡沫细胞计数。分别使用RT-PCR和Western-blot的方法检测各组PPARγ、ACAT1、SR-A1、ABCA1/G1基因和蛋白表达。
结果与阳性对照组相比,SP600125干预后不仅呈浓度依赖性地抑制C.pn感染对PPARy表达的下调,而且呈浓度依赖性地抑制C.pn感染调控的PPARy的下游靶基因SR-A1、ACAT1、ABCA1/G1的表达(p<0.05)。提示JNK参与了C.pn通过PPARy信号通路调控SR-A1、ACAT1、ABCA1/G1的表达,破坏胆固醇代谢稳态的过程。
结论C.pn部分通过JNK-PPARy信号通路,上调SR-A1、ACAT1基因和蛋白表达,下调ABCA1/G1基因和蛋白表达,增加胆固醇摄入和胆固醇酯合成,减少胆固醇流出,从而诱导THP-1源性巨噬细胞胆固醇代谢稳态的失衡。这可能为我们进一步探讨C.pn感染促进动脉粥样硬化的机制提供新的理论依据。
PartⅠEffects of Chlamydia pneumoniae infection on the Cholesterol Metabolism In THP-1-derived macrophages
Objective To observe the effects of Chlamydia pneumoniae (C.pn) infection on the cholesterol metabolism in THP-1-derived macrophages.
Methods C.pn strain AR-39 was propagated in HEp-2 cells by centrifugation-driven infection. The human THP-1 monocytic leukemia cell line differentiated to macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h, and then were randomly allocated into five groups:①control group;②-⑤different concentrations(1×105,4×105,5×105 and 1×106 IFU) of C.pn infection group; each group was incubated with 50μg/ml LDL for 48 h. The infection of C.pn on THP-1-derived macrophages was figured by transmission electron microscope. Lipid droplets in cytoplasm and the number of foam cells were observed by oil red O staining. The contents of intracellular total cholesterol (TC) and cholesteryl esters (CE) were measured by enzymic chromatometry. The mRNA and protein
expressions of scavenger receptor A1 (SR-A1), acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), ATP binding cassette transporter Al (ABCA1) and G1 (ABCG1) from each group were determined by RT-PCR and Western-blot, respectively.
Results Compared with control group, C.pn infection increased the contents of intracellular lipid droplets, the number of foam cells, TC and CE in a concentration-dependent manner. Moreover, C.pn infection not only up-regulated the mRNA and protein expressions of SR-A1 and ACAT1, but also down-regulated the mRNA and protein expressions of ABCA1 and ABCG1 in a concentration-dependent manner in LDL-treated THP-1 macrophages (all p<0.05). Higher concentrations of C.pn infection (5×105 and 1×106 IFU) group obviously cause the effects as mentioned above (p<0.05).
Conclusion C.pn infection may destroy the homeostasis of intracellular cholesterol metabolism by increasing SR-A1 and ACAT1 expressions, and inhibiting ABCA1 and ABCG1 expressions in LDL-treated THP-1-derived macrophages, which leads to foam cell formation.
Part II The role of peroxisome proliferator-activated receptor y pathway in Chlamydia pneumoniae-induced imbalance of cholesterol metabolism homeostasis
Objective To investigate the effects of peroxisome proliferator-activated receptor y (PPAR y) on the expressions of SR-A1, ACAT1, ABCA1 and ABCG1 regulated by Chlamydia pneumoniae (C.pn) infection, and to discuss the pathways of C.pn-induced imbalance of cholesterol metabolism homeostasis.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for 48 h. and then were randomly allocated into seven groups:①control group,50μg/ml low density lipoprotein (LDL) for 48 h;②C.pn infection group,50μg/ml LDL plus 1×106 IFU C.pn infection for 48 h;③Rosiglitazone (a specific PPARγligand) plus C.pn infection group, pretreatment with different concentrations of rosiglitazone (1、10、20μmol/L) for 2 h,50μg/ml LDL plus 1×106 IFU C.pn infection for 48 h;④Rosiglitazone group,20μmol/L rosiglitazone for 48 h. Lipid droplets in cytoplasm and the number of foam cells were observed by oil red O staining. The contents of intracellular cholesteryl esters were detected by enzymic chromatometry. The mRNA and protein expressions of PPARγ, SR-A1, ACAT1, ABCA1 and ABCG1 were determined by RT-PCR and Western-blot, respectively.
Results C.pn infection suppressed the expression of PPARγat mRNA and protein levels in concentration-dependent manner in LDL-treated THP-1 macrophages (all p <0.05). From morphological and biochemical criteria, higher concentrations of rosiglitazone (10 and 20μmol/L) markedly inhibited C.pn-induced imbalance of cholesterol metabolism homeostasis and foam cell formation. 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 at mRNA and protein levels by C.pn infection were concentration-dependently inhibited by rosiglitazone (all p<0.05).
Conclusion C.pn infection induces imbalance of cholesterol metabolism homeostasis and foam cell formation in THP-1 derived macrophages by up-regulating SR-A1 and ACAT1 expressions and down-regulating ABCA1 and ABCG1 expressions partly via PPAR y-dependent pathway.
PartⅢThe role of c-Jun NH2 terminal kinase pathway in Chlamydia pneumoniae-induced imbalance of cholesterol metabolism homeostasis
Objective To investigate the effects of c-Jun NH2 terminal kinase (JNK) on the expressions of SR-A1, ACAT1, ABCA1 and ABCG1 regulated by Chlamydia pneumoniae (C.pn) infection, and to discuss the pathways of C.pn-induced imbalance of cholesterol metabolism homeostasis.
Methods THP-1 monocytes were induced into macrophages by 160 nmol/L PMA for 48 h. and then were randomly allocated into seven groups:①control group,50μg/ml low density lipoprotein (LDL) for 48 h;②different concentrations of C.pn infection group,50μg/ml LDL plus 1×105,4×105,5×105 and 1×106 IFU C.pn infection for 48 h;③SP600125 (a specific JNK inhibitor) plus C.pn infection group, pretreatment with different concentrations of (1、10、20μmol/L) for 2 h,50μg/ml LDL plus 1×106 IFU C.pn infection for 48 h;④SP600125 group,20μmol /L SP600125 for 48 h. Lipid droplets in cytoplasm and the number of foam cells were observed by oil red O staining. The contents of intracellular cholesteryl esters were detected by enzymic chromatometry. The mRNA and protein expressions of PPARγ, SR-A1, ACAT1, ABCA1 and ABCG1 were determined by RT-PCR and Western-blot, respectively.
Results From morphological and biochemical criteria, higher concentrations of SP600125 (10 and 20μmol/L) markedly inhibited C.pn-induced imbalance of cholesterol metabolism homeostasis and foam cell formation. Compared with C.pn infection group, not only the down-regulation of PPAR y, but also the regulation of the taget genes of PPAR y (SR-A1, ACAT1, ABCA1 and ABCG1) at mRNA and protein levels by C.pn infection were concentration-dependently inhibited by SP600125(all p<0.05).
Conclusion C.pn infection induces imbalance of cholesterol metabolism homeostasis and foam cell formation in THP-1 derived macrophages by up-regulating SR-A1 and ACAT1 expressions and down-regulating ABCA1 and ABCG1 expressions partly via JNK-PPARγdependent pathway.
引文
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