紫外线致皮肤成纤维细胞和角质形成细胞中的自噬研究
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摘要
探讨中波紫外线(ultraviolet B, UVB)照射人皮肤成纤维细胞诱导的自噬对细胞凋亡活性的影响。通过单丹磺酰戊二胺(Monodansylcadaverine, MDC)染色和免疫荧光标记微管相关蛋白1轻链3(light chain3, LC3)的方法,确定不同剂量3-甲基腺嘌呤(3-methyladenine3-MA)对自噬的抑制作用。UVB照射后立即使用0.5mmol/L3-MA孵育细胞4h作为自噬的抑制方法。Hoechst和碘化丙啶(propidium iodide, PI)染色结合Annexin V-异硫氰酸荧光素(fluorescein isothiocyanate, FITC)和PI标记细胞后流式细胞术作为凋亡的分析方法。0.5mmol/L3-MA能明显抑制人皮肤成纤维细胞自噬活性(饥饿诱导组自噬细胞阳性百分数为63.037%±5.876%,3-MA孵育后下降至34.425%±5.183%)。0.5mmol/L3-MA对细胞活性影响最小。50mJ/cm2照射剂量下3-MA孵育较未孵育细胞强Hoechst和强PI双染细胞增多；100mJ/cm2照射剂量下3-MA孵育较未孵育细胞强Hoechst和强PI双染细胞减少。在50mJ/cm2照射剂量下,抑制自噬的细胞的中晚期凋亡细胞百分比(10.933±0.839)较未抑制细胞(7.267±0.473)上升,两者之间差异具有统计学意义(t=5.197,P=<0.05)；而在100mJ/cm2照射剂量下,抑制自噬的细胞的中晚期凋亡水平(7.100±0.781)较未抑制细胞(10.133±0.681)下降,两者之间差异具有统计学意义(t=6.286, P<0.05)。UVB诱导的人皮肤成纤维细胞自噬在50mJ/cm2照射剂量下通过抑制凋亡对细胞起到保护作用,而在100mJ/cm2照射剂量下发生的较高水平白噬可能诱导了自噬性细胞死亡。
观察慢性紫外线损伤对小鼠皮肤角质形成细胞凋亡和自噬交互调控元件Bax、 Bcl-2、Beclin-1及半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)的调控效应。采用模拟日光的UV对实验小鼠进行照射,设立对照。照射从最小红斑量(UVB0.07J/cm2,长波紫外线(ultraviolet A, UVA)0.7J/cm2)开始,1次/d,每周增加0.5个红斑量,每周照射5天,共9周,UVB总剂量达9.45J/cm2, UVA总剂量达94.5J/cm2,应用免疫组化法分别对实验前后(W0和W9) Bax、Bcl-2、Beclin-1和Caspase-3的表达进行检测,表达强度以免疫反应强度分布指数(immunoreactivity intensity distribution index, IRIDI)表示。在损伤组,照光(?)(?) Beclin-1、Caspase-3、Bax、Bcl-2的表达计分均值(范围)分别为0.30(0-2)、0.25(0-2)、0.35(0-2)、0.25(0-1),照光后计分分别为2.70(2-6)、3.30(2-9)、3.35(2-6)、0.25(0-1)。损伤组小鼠表皮角质形成细胞中Beclin-1、Caspase-3、Bax蛋白表达显著升高,且差异有统计学意义(P均<0.05),Bcl-2蛋白表达变化不明显,且无统计学意义(P>0.05)。损伤组W9时Beclin-1和Bax的表达明显高于Bcl-2(P均<0.05)。在同时期正常饲养小鼠Beclin-1、Caspase-3. Bax、Bcl-2的均值(范围)在W0为0.20(0-1)、0.20(0-1)、0.30(0-1)、0.20(0-1),W9则为0.30(0-1)、0.20(0-1)、0.30(0-1)、0.10(0-1)。分析发现Beclin-1、Caspase-3、Bax、Bcl-2表达无统计学意义上的表达差异(P>0.05)。慢性UV损伤对小鼠皮肤角质形成细胞中凋亡和自噬的交互调控元件Beclin-1和Bax具有上调表达的作用,而对另一元件Bcl-2表达调控效应不显著。这一系列的调控效应可能参与了凋亡和自噬在慢性UV皮肤损伤中的交互调控。
研究UVB照射对体外培养的HaCaT细胞自噬的调控效应。使用由低到高三种剂量照射HaCaT细胞后继续培养4小时,使用透射电镜进行细胞超微结构分析,并使用蛋白免疫印迹方法进行LC3-Ⅰ→Ⅱ型转换分析。结果发现小剂量和中等剂量的UVB照射后,细胞内可出现自噬体,并且在小剂量照射后更为多见；然而,当接受了高剂量照射后,细胞中不能发现此类的结构。小剂量UVB照射后,LC3-Ⅱ的蛋白表达量升高；中等剂量UVB照射对LC3-Ⅱ的蛋白表达量没有产生显著的变化；而高剂量的UVB照射产生了对LC3-Ⅱ的蛋白表达显著下调。研究结果提示小剂量UVB单次照射对角质形成细胞具有诱导自噬的效应,而高剂量的UVB单次照射产生了抑制自噬的效应。
For investigating the interaction between apoptosis and autophagy which induced by different doses of ultraviolet B radiation in human skin fibroblast, the first part of this study has been designed. Inhibition effect by3-MA incubation was confirmed by MDC staining and LC3expression calibrated by immunofluorescence. The method of inhibition of autophagy was used by incubation4h with0.5mmol/L3-MA after different doses of UVB radiation immediately. The qualitative and quantitive methods of apoptosis assay were performed by fluorescence staining with Hoechst accompanied with PI and flow cytometry stained with Annexin V-FITC and PI. Fibroblast incubated with0.5mmol/L3-MA presented obvious inhibition of autophagy and low impairment on cell viability. The percentage of autophagic cell descended from63.037±5.876, which were induced by starvation, to34.425±5.183. The intensity of fluorescence which reflected expression of LC3increased gradually followed by increase of the UVB radiation doses, however the increase of intensity of fluorescence attenuated after inhibition autophagy by3-MA. Under radiation of50mJ/cm2dose, inhibition of fibroblast autophagy resulted in elevation of intermedial and non-viable apoptosis. Hoechst and PI staining showed increase of cells which showed both strong blue and red fluorescence. Flow cytometry assay revealed that increase of cells which stained with Annexin V-FITC and PI, from7.267±0.473to10.933±0.839. The difference has statistical significance (t=-5.197, P=0.035<0.05). On the contrary, under radiation of100mJ/cm2dose, inhibition of autophagy resulted in descent of intermedial and non-viable apoptosis. Hoechst and PI assay showed that decrease of cells which showed both strong blue and red fluorescence. Flow cytometry assay revealed that decrease of cells which stained with Annexin V-FITC and PI, from10.133±0.681to7.100±0.781. The difference has statistical significance (t=6.286, P=0.024<0.05). Fibroblast autophagy induced by50mJ/cm2UVB radiation has the pro-survival effect by inhibition of apoptosis.100mJ/cm2UVB radiation on fibroblast maybe induce autophagic cell death.
The aim of the second part of this study is to investigate the expression of Bax、Bcl-2、 Caspase-3and Beclin-1, which were regulatory elements involved in cross-talk between apoptosis and autophagy, within keratinocytes of mice skin exposed chronic ultraviolet irradiation. We have constituted the model of chronic UV-damaged mice, which were irradiated UVA plus UVB simulated solar light. The irradiation began form the MED
(UVB0.07J/cm2, UVA0.7J/cm2), and increased0.5MED per week. The protocol contained1irradiation per day,5irradiation per week, total9weeks, as well as UVB9.45J/cm2and UVA94.5J/cm2of total dose. The expression of Bax、Bcl-2、Caspase-3and Beclin-1was investigated in epidermal keratinocytes of two groups through immunohistochemical study and analyzed contrastively between the starting point and end point of this research. Wilcoxon signed ranks text was performed for statistics. The average value for Bax、Bcl-2、Caspase-3and Beclin-1was0.30(0-2)、0.25(0-2)、0.35(0-2)、0.25(0-1) respectively in chronic UV-damaged group before UV irradiation. The average value for Bax、Bcl-2、Caspase-3and Beclin-1was2.70(2-6)、3.30(2-9)、3.35(2-6) and0.25(0-1) respectively after UV irradiation. There was significance difference in expression of Bax、Caspase-3and Beclin-1(P<0.05), but no statistical difference in expression of Bel-2(P>0.05). The average value for Bax、Bcl-2、Caspase-3and Beclin-1was0.20(0-1)、0.20(0-1)、0.30(0-1)、0.20(0-1) respectively in control group at the beginning of study, and the average value for Bax、Bcl-2、Caspase-3and Beclin-1was0.30(0-1)、0.20(0-1)、0.30(0-1)、0.10(0-1) respectively at the end of study. There was no statistical difference in expression of Bax、Bcl-2、Caspase-3and Beclin-1(P>0.05). Chronic UV irridiation can up-regulate the expression of Beclin-1and Bax which both are involved in cross-talk between apoptosis and autophagy. It may play a role in cross-talk of apoptosis and autophagy in chronic skin photodamage.
The third part of this study was designed to investigate the regulation of autophagy in human keratinocyte cell line, HaCaT suffering from UVB irradiation. At the point of fourth hour after three different doses of UVB irradiation from low to high, HaCaT cells were performed ultrastructural analysis through transmission electron microscopy and investigation of LC3-Ⅱ expression by immunoblotting. Lots of double-membrane structures, the content of which was similar to cytoplasm, were observed in the cytoplasm exposed to low dose of UVB. Degraded organelles can be found in some of these structures. The quantity of these structures in cells exposed to medium dose of UVB also can be found but not as more as that in cells exposed to low dose. However, this structure was hardly seen in cells exposed to high dose of UVB. Accordingly, expression of LC3-Ⅱ was up-regulated in HaCaT suffering from low dose of UVB irradiation, and down-regulated by high dose of UVB. These findings demonstrated that autophagy in keratinocyte was induced by low dose of UVB irradiation, but inhibited by high dose of UVB irradiation.
观察慢性紫外线损伤对小鼠皮肤角质形成细胞凋亡和自噬交互调控元件Bax、 Bcl-2、Beclin-1及半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)的调控效应。采用模拟日光的UV对实验小鼠进行照射,设立对照。照射从最小红斑量(UVB0.07J/cm2,长波紫外线(ultraviolet A, UVA)0.7J/cm2)开始,1次/d,每周增加0.5个红斑量,每周照射5天,共9周,UVB总剂量达9.45J/cm2, UVA总剂量达94.5J/cm2,应用免疫组化法分别对实验前后(W0和W9) Bax、Bcl-2、Beclin-1和Caspase-3的表达进行检测,表达强度以免疫反应强度分布指数(immunoreactivity intensity distribution index, IRIDI)表示。在损伤组,照光(?)(?) Beclin-1、Caspase-3、Bax、Bcl-2的表达计分均值(范围)分别为0.30(0-2)、0.25(0-2)、0.35(0-2)、0.25(0-1),照光后计分分别为2.70(2-6)、3.30(2-9)、3.35(2-6)、0.25(0-1)。损伤组小鼠表皮角质形成细胞中Beclin-1、Caspase-3、Bax蛋白表达显著升高,且差异有统计学意义(P均<0.05),Bcl-2蛋白表达变化不明显,且无统计学意义(P>0.05)。损伤组W9时Beclin-1和Bax的表达明显高于Bcl-2(P均<0.05)。在同时期正常饲养小鼠Beclin-1、Caspase-3. Bax、Bcl-2的均值(范围)在W0为0.20(0-1)、0.20(0-1)、0.30(0-1)、0.20(0-1),W9则为0.30(0-1)、0.20(0-1)、0.30(0-1)、0.10(0-1)。分析发现Beclin-1、Caspase-3、Bax、Bcl-2表达无统计学意义上的表达差异(P>0.05)。慢性UV损伤对小鼠皮肤角质形成细胞中凋亡和自噬的交互调控元件Beclin-1和Bax具有上调表达的作用,而对另一元件Bcl-2表达调控效应不显著。这一系列的调控效应可能参与了凋亡和自噬在慢性UV皮肤损伤中的交互调控。
研究UVB照射对体外培养的HaCaT细胞自噬的调控效应。使用由低到高三种剂量照射HaCaT细胞后继续培养4小时,使用透射电镜进行细胞超微结构分析,并使用蛋白免疫印迹方法进行LC3-Ⅰ→Ⅱ型转换分析。结果发现小剂量和中等剂量的UVB照射后,细胞内可出现自噬体,并且在小剂量照射后更为多见；然而,当接受了高剂量照射后,细胞中不能发现此类的结构。小剂量UVB照射后,LC3-Ⅱ的蛋白表达量升高；中等剂量UVB照射对LC3-Ⅱ的蛋白表达量没有产生显著的变化；而高剂量的UVB照射产生了对LC3-Ⅱ的蛋白表达显著下调。研究结果提示小剂量UVB单次照射对角质形成细胞具有诱导自噬的效应,而高剂量的UVB单次照射产生了抑制自噬的效应。
For investigating the interaction between apoptosis and autophagy which induced by different doses of ultraviolet B radiation in human skin fibroblast, the first part of this study has been designed. Inhibition effect by3-MA incubation was confirmed by MDC staining and LC3expression calibrated by immunofluorescence. The method of inhibition of autophagy was used by incubation4h with0.5mmol/L3-MA after different doses of UVB radiation immediately. The qualitative and quantitive methods of apoptosis assay were performed by fluorescence staining with Hoechst accompanied with PI and flow cytometry stained with Annexin V-FITC and PI. Fibroblast incubated with0.5mmol/L3-MA presented obvious inhibition of autophagy and low impairment on cell viability. The percentage of autophagic cell descended from63.037±5.876, which were induced by starvation, to34.425±5.183. The intensity of fluorescence which reflected expression of LC3increased gradually followed by increase of the UVB radiation doses, however the increase of intensity of fluorescence attenuated after inhibition autophagy by3-MA. Under radiation of50mJ/cm2dose, inhibition of fibroblast autophagy resulted in elevation of intermedial and non-viable apoptosis. Hoechst and PI staining showed increase of cells which showed both strong blue and red fluorescence. Flow cytometry assay revealed that increase of cells which stained with Annexin V-FITC and PI, from7.267±0.473to10.933±0.839. The difference has statistical significance (t=-5.197, P=0.035<0.05). On the contrary, under radiation of100mJ/cm2dose, inhibition of autophagy resulted in descent of intermedial and non-viable apoptosis. Hoechst and PI assay showed that decrease of cells which showed both strong blue and red fluorescence. Flow cytometry assay revealed that decrease of cells which stained with Annexin V-FITC and PI, from10.133±0.681to7.100±0.781. The difference has statistical significance (t=6.286, P=0.024<0.05). Fibroblast autophagy induced by50mJ/cm2UVB radiation has the pro-survival effect by inhibition of apoptosis.100mJ/cm2UVB radiation on fibroblast maybe induce autophagic cell death.
The aim of the second part of this study is to investigate the expression of Bax、Bcl-2、 Caspase-3and Beclin-1, which were regulatory elements involved in cross-talk between apoptosis and autophagy, within keratinocytes of mice skin exposed chronic ultraviolet irradiation. We have constituted the model of chronic UV-damaged mice, which were irradiated UVA plus UVB simulated solar light. The irradiation began form the MED
(UVB0.07J/cm2, UVA0.7J/cm2), and increased0.5MED per week. The protocol contained1irradiation per day,5irradiation per week, total9weeks, as well as UVB9.45J/cm2and UVA94.5J/cm2of total dose. The expression of Bax、Bcl-2、Caspase-3and Beclin-1was investigated in epidermal keratinocytes of two groups through immunohistochemical study and analyzed contrastively between the starting point and end point of this research. Wilcoxon signed ranks text was performed for statistics. The average value for Bax、Bcl-2、Caspase-3and Beclin-1was0.30(0-2)、0.25(0-2)、0.35(0-2)、0.25(0-1) respectively in chronic UV-damaged group before UV irradiation. The average value for Bax、Bcl-2、Caspase-3and Beclin-1was2.70(2-6)、3.30(2-9)、3.35(2-6) and0.25(0-1) respectively after UV irradiation. There was significance difference in expression of Bax、Caspase-3and Beclin-1(P<0.05), but no statistical difference in expression of Bel-2(P>0.05). The average value for Bax、Bcl-2、Caspase-3and Beclin-1was0.20(0-1)、0.20(0-1)、0.30(0-1)、0.20(0-1) respectively in control group at the beginning of study, and the average value for Bax、Bcl-2、Caspase-3and Beclin-1was0.30(0-1)、0.20(0-1)、0.30(0-1)、0.10(0-1) respectively at the end of study. There was no statistical difference in expression of Bax、Bcl-2、Caspase-3and Beclin-1(P>0.05). Chronic UV irridiation can up-regulate the expression of Beclin-1and Bax which both are involved in cross-talk between apoptosis and autophagy. It may play a role in cross-talk of apoptosis and autophagy in chronic skin photodamage.
The third part of this study was designed to investigate the regulation of autophagy in human keratinocyte cell line, HaCaT suffering from UVB irradiation. At the point of fourth hour after three different doses of UVB irradiation from low to high, HaCaT cells were performed ultrastructural analysis through transmission electron microscopy and investigation of LC3-Ⅱ expression by immunoblotting. Lots of double-membrane structures, the content of which was similar to cytoplasm, were observed in the cytoplasm exposed to low dose of UVB. Degraded organelles can be found in some of these structures. The quantity of these structures in cells exposed to medium dose of UVB also can be found but not as more as that in cells exposed to low dose. However, this structure was hardly seen in cells exposed to high dose of UVB. Accordingly, expression of LC3-Ⅱ was up-regulated in HaCaT suffering from low dose of UVB irradiation, and down-regulated by high dose of UVB. These findings demonstrated that autophagy in keratinocyte was induced by low dose of UVB irradiation, but inhibited by high dose of UVB irradiation.
引文
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