TRPV1在角质形成细胞释放炎症介质中的作用及药物的干预研究
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摘要
皮肤是机体最大的器官。角质形成细胞是其主要组成成分,是保护体内器官免受外界环境有害物质刺激的重要生理屏障。大量研究显示角质形成细胞在一些炎症性皮肤病的发病机制中发挥重要作用。一旦受到外界因素和细胞因子的刺激,皮肤角质形成细胞能分泌多种炎症因子,从而积极地参与机体炎症和免疫反应。如角质形成细胞参与变应性接触性皮炎发生、发展的全过程。在一些遗传因素相关的皮肤病,如特应性皮炎,角质形成细胞成分可作为免疫佐剂参与疾病发生,并分泌过量的趋化因子和细胞因子,影响细胞生长与分化,也可以通过自分泌和旁分泌机制影响皮肤中其他细胞,促进疾病发生与发展。
TRPV1(transient receptor potential vanilloid receptor-1)是TRP家族成员,是一种钙通道蛋白,人和大鼠的TRPV1已经被克隆。最初的研究发现TRPV1是表达于外周初级传入神经元上重要的伤害感受器,参与了急性炎症痛敏的形成。TRPV1可以被内源性、外源性香草醛类物质,热刺激,酸,炎症刺激和组织损伤等激活。TRPV1不仅存在于神经元细胞,还广泛存在于非神经细胞上,例如呼吸道上皮细胞,心肌细胞,膀胱上皮细胞,胃壁上皮细胞和角质形成细胞。角质形成细胞中TRPV1受体的功能尤其是在皮肤神经网络中的作用受到重视,因此也被看作是开发抗炎和镇痛药物的新的靶点。多种伤害性刺激通过直接诱导角质形成细胞,触发了表皮的炎症反应,升高了致炎因子和缓激肽等炎症介质的水平。在人表皮角质形成细胞中TRPV1的活化能直接导致环氧酶-2的释放。研究发现,在人的鼻、气管和肺上皮细胞中TRPV1在辣椒素(CAP)的作用下活化,能够介导人上皮细胞中IL-6基因和蛋白表达水平的上调。说明TRPV1可能在角质形成细胞等非神经细胞分泌炎症因子参与炎症反应过程中发挥重要作用。针对TRPV1的药物研究也将为皮肤炎症性疾病的治疗带来新的前景。
为揭示角质形成细胞表达TRPV1的生物学功能,我们检测了分离的人角质形成细胞和HaCaT细胞炎症介质表达与TRPV1之间的关系。同时还研究了TRPV1活化后细胞内钙离子的变化。利用瞬时转染和双荧光素酶检测技术探讨了TRPV1活化与NFκB活化的关系。在此基础上,考察了临床用于抗炎镇痛的皂苷类活性成分对TRPV1表达及炎症介质分泌的影响。
主要研究结果如下:
1. TRPV1mRNA在人角质形成细胞中有表达,且在CAP刺激下表达增加。经ELISA法检测,CAP显著升高了致炎因子IL-8和PGE2的表达水平,且呈剂量依赖性。8μmol/L CAP可以使角质形成细胞IL-8显著升高62.75%,使PGE2升高54.73%。这种作用能够被TRPV1受体拮抗剂CPZ抑制,说明TRPV1活化促进了致炎因子的表达。
2.经流式细胞仪检测荧光探针的方法,发现2～16μmol/L CAP能剂量依赖性增加HaCaT细胞内钙离子浓度。而3μmol/L CPZ、10μmol/L CPZ和20μmol/L CPZ分别使CAP刺激升高的荧光强度降低了32.11%、38.33%和34.66%。CPZ的抑制作用表明,TRPV1活化导致胞内钙离子浓度的改变。
3.经流式细胞仪和western blot方法鉴定,成功构建了能够稳定表达TRPV1蛋白的HEK293T细胞株。利用该细胞株研究证实,TRPV1介导了CAP刺激HEK 293T-TRPV1细胞内钙离子浓度升高,主要是细胞外钙离子内流的结果。
4.利用瞬时转染及双荧光素酶检测技术,将pNFκB和pRL-TK质粒共同转染HEK293T细胞、HaCaT细胞和HEK 293T-TRPV1细胞,比较三种细胞经CAP刺激后NFκB的活化水平。结果表明CAP能够显著增强经瞬时转染的HaCaT细胞和HEK 293T-TRPV1细胞中NFκB转录活性,而HEK293T细胞中无明显变化。TRPV1受体拮抗剂能够抑制CAP诱导NFκB活化的作用,说明TRPV1活化后进一步通过信号的传递诱导了NFκB的激活。
5.利用特异性PI3K和MAPK信号途径抑制剂,分别阻断该两条信号传导通路,发现PD98059、Wortmannin分别使HEK 293T-TRPV1细胞的NFκB转录活性降低了52.42%、24.52%,经统计分析,有显著差异(P<0.05)。说明TRPV1活化促进NFκB激活的作用与MAPK和PI3K信号传递途径有关。
6.人参皂苷Rb1能够显著降低HaCaT细胞中CAP诱导的TRPV1 mRNA表达,抑制对NFκB的活化作用,使炎症因子IL-8、IL-6和PGE2的分泌水平分别下降26.72%、38.23%和57.01%。在HEK293T-TRPV1细胞株中,Rb1能够显著降低CAP诱导细胞内钙离子浓度,特异地抑制CAP诱导的NFκB活化。由此可见,Rb1能够抑制TRPV1受体而发挥作用。
7.芍药苷(PF)能够显著降低CAP升高的IL-8、IL-6、PGE2水平,下降了11.39%、51.96%。75.98%。比较PF对HaCaT细胞和HEK293T-TRPV1细胞株经CAP诱导升高的细胞内钙离子的干预作用,表明PF可能存在其他的通道影响钙离子内流,而不是直接与TRPV1相关的。
8. CAP对细胞分泌TNFα影响不显著。三七皂苷R1和人参皂苷Rg1对CAP依赖的TRPV1受体活化、钙离子内流及信号传递通路没有明显干预作用。
9.经二维电泳分析和MALDI-TOF-MS鉴定发现,CAP刺激HaCaT细胞表达差异蛋白有磷酸甘油醛异构酶,烯醇化酶1和角蛋白14,其在TRPV1活化后致炎症介质表达中的作用,有待于进一步研究。
Skin is the largest organ of human body, covering the entire body surface. Keratinocytes are its major component, by making keratin protein, function as a protective barrier against exogenous stimuli. As Keratinocytes have been demonstrated to produce various kinds of cytokines, skin plays an important role in immunologic and inflammatory responses of the body. Evidence is accumulating to show the significant contribution of cytokines to the pathogenesis or severity of certain diseases. Keratinocytes are activated by environmental stimuli to produce a variety of cytokines that can affect the immune response as well as the cell growth and differentiation of Keratinocytes themselves and other cell components in the skin in an autocrine or paracrine fashion.
TRPV1 (transient receptor potential vanilloid receptor subtype 1) is a member of TRP family. The receptor is a nonselective cationic channel and both rat and human TRPV1 were recently cloned. TRPV1 is activated by capsaicin, heat and protons, and can be hypersensitized by injury. These findings indicate that TRPV1 acts as a pivotal molecular integrator of noxious chemical and thermal stimuli in the peripheral terminals of primary afferents involved in nociception and inflammation. Therefore, the presence of functional TRPV1 receptors in keratinocytes has generated interest in skin–nerve crosstalk under physiological and pathological conditions. It has become a promising target for the development of a new generation of anti-inflammatory and analgesic agents.
TRPV1 expression has been identified in non-neuronal cells as well as neuronal cells, for example in bronchial epithelial cells, cardiomyocytes, urinary bladder epithelial cells, gastric epithelial cells, oral epithelium, keratinocytes. Activation of TRPV1 in human keratinocytes by capsaicin results in a dose-dependent expression of cyclooxygenase-2. Capsaicinoids cause the calcium-dependent production of IL-6 and calcium- independent cell death via TRPV1 in cultured human lung cells and primary cultured human airway epithelial cells. These findings suggest that TRPV1 plays a key role in inflammation by producing various cytokines in non-neuronal cells. The biological role of the receptors in each of these cells remains elusive. Understanding the regulatory pathways of TRPV1 activation in keratinocyte will offer a great potential for treating skin diseases such as genetic abnormalities, infections, and skin cancer. The mechanism of TRPV1 in inflammation should be to study. The drugs target at TRPV1 will bring a bright future to producing therapeutics for the inflammation diseases of skin targeting human TRPV1.
In the study, in order to clarify the physiological role of TRPV1 in non-neuronal tissues of the human skin, we examined inflammatory mediators’expression and relationship with the expression of TRPV1 in normal human skin keratinocytes and HaCaT cells stimulated with CAP. The intercellular Ca2+ concentration changes and NFκB activation were examined by FCM and Dual Luciferase Assay System. The effect of drugs on the production of pro-inflammation mediators, Ca2+ concentration changes and NFκB activation from primary cultured human keratinocytes and HaCat cells were also invesgated.
The results are shown as followed:
1. The effect of capsaicin on TRPV1 mRNA induction in primary skin keratinocytes and HaCaT cells was assessed by Reverse Transcript PCR. The TRPV1 mRNA level increased by CAP. The concentration of IL-8 and PGE2 protein in the keratinocytes culture medium evaluated by ELISA, was increased 62.75% and 54.72% treated by CAP. The capsaicin-mediated accumulation of IL-8 and PGE2 production was concentration-dependent. Capsazepine significantly inhibited the 8μM capsaicin-mediated increase in IL-8 and PGE2 production.
2. Intracellular Calcium Levels were detected by FCM. 2-16μmol/L CAP increased the level of intracellular calcium by concentration-dependent manner. However, 3μmol/L CPZ、10μmol/L CPZ and 20μmol/L CPZ decreased the CAP induced related fluence ratio by 32.11%、38.33% and 34.66%.
3. The stably transfected HEK293T cells expression TRPV1 were constructed using Lipofectamine reagent. A stably transfected clone was also isolated by selection in G418, identified by FCM and Western blotting. The intracellular Calcium Levels were induced by CAP via TRPV1 activation, and extracllular calcium result in the elevation.
4. The pNFκB and pRL-TK plsamids were transiently transfected to HEK293T cells, HaCaT cells and HEK 293T stably expression of TRPV1, respectively. The related NFκB activation ratio was invesgated by Dual Luciferase Assay System. The result showed that CAP can significantly increase the related NFκB activation ratio in HaCaT cells and HEK 293T-TRPV1 cells. The HEK293T cells have not changed. CPZ, a TRPV1 antagonist, can decrease the related NFκB activation ratio.
5. Incubation the cells with PD98059 and Wortmannin before treated with CAP, the inhibitors of PI3K pathway and MAPK pathway can suppress the level of NFκB activation 52.42% and 24.52%,respectively. That indicated that CAP induced NFκB activation via PI3K pathway and MAPK pathway.
6. Ginsenoside Rb1 significantly decreased the expression level of TRPV1 mRNA and the activation of NFκB in HaCaT cells induced by CAP, as well as inhibited the secretion of IL-8、IL-6 and PGE2 by 26.72%、38.23% and 57.01%.
7. Paeoniflorin significantly decreased secretion of IL-8、IL-6 and PGE2 induced by CAP in HaCaT cells 11.39%、51.96%。75.98%. The effects of PF are different on the calcium influx in between HaCaT cells and HEK293T-TRPV1 cells, which suggested that PF was not directly effect calcium influx through the TRPV1 channel.
8. CAP has no significant influence on the production of TNFα. Notoginsenoside R1 and Ginsenoside Rg1 has no significant influence on the TRPV1 activation, calcium influx and signal transfer pass way.
9. The result of TRPV1 stimulated by CAP was shown by proteomic technology to find the unreported proteins related with the function of TRPV1. As a result of MOLDI-TOF MS/MS, Triosephosphate isomerase, enolase 1 variant and KERATIN 14 in HaCaT cells treated with CAP have significant changed. The function and role of these proteins on the inflammation in skin should be investigated further.
TRPV1(transient receptor potential vanilloid receptor-1)是TRP家族成员,是一种钙通道蛋白,人和大鼠的TRPV1已经被克隆。最初的研究发现TRPV1是表达于外周初级传入神经元上重要的伤害感受器,参与了急性炎症痛敏的形成。TRPV1可以被内源性、外源性香草醛类物质,热刺激,酸,炎症刺激和组织损伤等激活。TRPV1不仅存在于神经元细胞,还广泛存在于非神经细胞上,例如呼吸道上皮细胞,心肌细胞,膀胱上皮细胞,胃壁上皮细胞和角质形成细胞。角质形成细胞中TRPV1受体的功能尤其是在皮肤神经网络中的作用受到重视,因此也被看作是开发抗炎和镇痛药物的新的靶点。多种伤害性刺激通过直接诱导角质形成细胞,触发了表皮的炎症反应,升高了致炎因子和缓激肽等炎症介质的水平。在人表皮角质形成细胞中TRPV1的活化能直接导致环氧酶-2的释放。研究发现,在人的鼻、气管和肺上皮细胞中TRPV1在辣椒素(CAP)的作用下活化,能够介导人上皮细胞中IL-6基因和蛋白表达水平的上调。说明TRPV1可能在角质形成细胞等非神经细胞分泌炎症因子参与炎症反应过程中发挥重要作用。针对TRPV1的药物研究也将为皮肤炎症性疾病的治疗带来新的前景。
为揭示角质形成细胞表达TRPV1的生物学功能,我们检测了分离的人角质形成细胞和HaCaT细胞炎症介质表达与TRPV1之间的关系。同时还研究了TRPV1活化后细胞内钙离子的变化。利用瞬时转染和双荧光素酶检测技术探讨了TRPV1活化与NFκB活化的关系。在此基础上,考察了临床用于抗炎镇痛的皂苷类活性成分对TRPV1表达及炎症介质分泌的影响。
主要研究结果如下:
1. TRPV1mRNA在人角质形成细胞中有表达,且在CAP刺激下表达增加。经ELISA法检测,CAP显著升高了致炎因子IL-8和PGE2的表达水平,且呈剂量依赖性。8μmol/L CAP可以使角质形成细胞IL-8显著升高62.75%,使PGE2升高54.73%。这种作用能够被TRPV1受体拮抗剂CPZ抑制,说明TRPV1活化促进了致炎因子的表达。
2.经流式细胞仪检测荧光探针的方法,发现2～16μmol/L CAP能剂量依赖性增加HaCaT细胞内钙离子浓度。而3μmol/L CPZ、10μmol/L CPZ和20μmol/L CPZ分别使CAP刺激升高的荧光强度降低了32.11%、38.33%和34.66%。CPZ的抑制作用表明,TRPV1活化导致胞内钙离子浓度的改变。
3.经流式细胞仪和western blot方法鉴定,成功构建了能够稳定表达TRPV1蛋白的HEK293T细胞株。利用该细胞株研究证实,TRPV1介导了CAP刺激HEK 293T-TRPV1细胞内钙离子浓度升高,主要是细胞外钙离子内流的结果。
4.利用瞬时转染及双荧光素酶检测技术,将pNFκB和pRL-TK质粒共同转染HEK293T细胞、HaCaT细胞和HEK 293T-TRPV1细胞,比较三种细胞经CAP刺激后NFκB的活化水平。结果表明CAP能够显著增强经瞬时转染的HaCaT细胞和HEK 293T-TRPV1细胞中NFκB转录活性,而HEK293T细胞中无明显变化。TRPV1受体拮抗剂能够抑制CAP诱导NFκB活化的作用,说明TRPV1活化后进一步通过信号的传递诱导了NFκB的激活。
5.利用特异性PI3K和MAPK信号途径抑制剂,分别阻断该两条信号传导通路,发现PD98059、Wortmannin分别使HEK 293T-TRPV1细胞的NFκB转录活性降低了52.42%、24.52%,经统计分析,有显著差异(P<0.05)。说明TRPV1活化促进NFκB激活的作用与MAPK和PI3K信号传递途径有关。
6.人参皂苷Rb1能够显著降低HaCaT细胞中CAP诱导的TRPV1 mRNA表达,抑制对NFκB的活化作用,使炎症因子IL-8、IL-6和PGE2的分泌水平分别下降26.72%、38.23%和57.01%。在HEK293T-TRPV1细胞株中,Rb1能够显著降低CAP诱导细胞内钙离子浓度,特异地抑制CAP诱导的NFκB活化。由此可见,Rb1能够抑制TRPV1受体而发挥作用。
7.芍药苷(PF)能够显著降低CAP升高的IL-8、IL-6、PGE2水平,下降了11.39%、51.96%。75.98%。比较PF对HaCaT细胞和HEK293T-TRPV1细胞株经CAP诱导升高的细胞内钙离子的干预作用,表明PF可能存在其他的通道影响钙离子内流,而不是直接与TRPV1相关的。
8. CAP对细胞分泌TNFα影响不显著。三七皂苷R1和人参皂苷Rg1对CAP依赖的TRPV1受体活化、钙离子内流及信号传递通路没有明显干预作用。
9.经二维电泳分析和MALDI-TOF-MS鉴定发现,CAP刺激HaCaT细胞表达差异蛋白有磷酸甘油醛异构酶,烯醇化酶1和角蛋白14,其在TRPV1活化后致炎症介质表达中的作用,有待于进一步研究。
Skin is the largest organ of human body, covering the entire body surface. Keratinocytes are its major component, by making keratin protein, function as a protective barrier against exogenous stimuli. As Keratinocytes have been demonstrated to produce various kinds of cytokines, skin plays an important role in immunologic and inflammatory responses of the body. Evidence is accumulating to show the significant contribution of cytokines to the pathogenesis or severity of certain diseases. Keratinocytes are activated by environmental stimuli to produce a variety of cytokines that can affect the immune response as well as the cell growth and differentiation of Keratinocytes themselves and other cell components in the skin in an autocrine or paracrine fashion.
TRPV1 (transient receptor potential vanilloid receptor subtype 1) is a member of TRP family. The receptor is a nonselective cationic channel and both rat and human TRPV1 were recently cloned. TRPV1 is activated by capsaicin, heat and protons, and can be hypersensitized by injury. These findings indicate that TRPV1 acts as a pivotal molecular integrator of noxious chemical and thermal stimuli in the peripheral terminals of primary afferents involved in nociception and inflammation. Therefore, the presence of functional TRPV1 receptors in keratinocytes has generated interest in skin–nerve crosstalk under physiological and pathological conditions. It has become a promising target for the development of a new generation of anti-inflammatory and analgesic agents.
TRPV1 expression has been identified in non-neuronal cells as well as neuronal cells, for example in bronchial epithelial cells, cardiomyocytes, urinary bladder epithelial cells, gastric epithelial cells, oral epithelium, keratinocytes. Activation of TRPV1 in human keratinocytes by capsaicin results in a dose-dependent expression of cyclooxygenase-2. Capsaicinoids cause the calcium-dependent production of IL-6 and calcium- independent cell death via TRPV1 in cultured human lung cells and primary cultured human airway epithelial cells. These findings suggest that TRPV1 plays a key role in inflammation by producing various cytokines in non-neuronal cells. The biological role of the receptors in each of these cells remains elusive. Understanding the regulatory pathways of TRPV1 activation in keratinocyte will offer a great potential for treating skin diseases such as genetic abnormalities, infections, and skin cancer. The mechanism of TRPV1 in inflammation should be to study. The drugs target at TRPV1 will bring a bright future to producing therapeutics for the inflammation diseases of skin targeting human TRPV1.
In the study, in order to clarify the physiological role of TRPV1 in non-neuronal tissues of the human skin, we examined inflammatory mediators’expression and relationship with the expression of TRPV1 in normal human skin keratinocytes and HaCaT cells stimulated with CAP. The intercellular Ca2+ concentration changes and NFκB activation were examined by FCM and Dual Luciferase Assay System. The effect of drugs on the production of pro-inflammation mediators, Ca2+ concentration changes and NFκB activation from primary cultured human keratinocytes and HaCat cells were also invesgated.
The results are shown as followed:
1. The effect of capsaicin on TRPV1 mRNA induction in primary skin keratinocytes and HaCaT cells was assessed by Reverse Transcript PCR. The TRPV1 mRNA level increased by CAP. The concentration of IL-8 and PGE2 protein in the keratinocytes culture medium evaluated by ELISA, was increased 62.75% and 54.72% treated by CAP. The capsaicin-mediated accumulation of IL-8 and PGE2 production was concentration-dependent. Capsazepine significantly inhibited the 8μM capsaicin-mediated increase in IL-8 and PGE2 production.
2. Intracellular Calcium Levels were detected by FCM. 2-16μmol/L CAP increased the level of intracellular calcium by concentration-dependent manner. However, 3μmol/L CPZ、10μmol/L CPZ and 20μmol/L CPZ decreased the CAP induced related fluence ratio by 32.11%、38.33% and 34.66%.
3. The stably transfected HEK293T cells expression TRPV1 were constructed using Lipofectamine reagent. A stably transfected clone was also isolated by selection in G418, identified by FCM and Western blotting. The intracellular Calcium Levels were induced by CAP via TRPV1 activation, and extracllular calcium result in the elevation.
4. The pNFκB and pRL-TK plsamids were transiently transfected to HEK293T cells, HaCaT cells and HEK 293T stably expression of TRPV1, respectively. The related NFκB activation ratio was invesgated by Dual Luciferase Assay System. The result showed that CAP can significantly increase the related NFκB activation ratio in HaCaT cells and HEK 293T-TRPV1 cells. The HEK293T cells have not changed. CPZ, a TRPV1 antagonist, can decrease the related NFκB activation ratio.
5. Incubation the cells with PD98059 and Wortmannin before treated with CAP, the inhibitors of PI3K pathway and MAPK pathway can suppress the level of NFκB activation 52.42% and 24.52%,respectively. That indicated that CAP induced NFκB activation via PI3K pathway and MAPK pathway.
6. Ginsenoside Rb1 significantly decreased the expression level of TRPV1 mRNA and the activation of NFκB in HaCaT cells induced by CAP, as well as inhibited the secretion of IL-8、IL-6 and PGE2 by 26.72%、38.23% and 57.01%.
7. Paeoniflorin significantly decreased secretion of IL-8、IL-6 and PGE2 induced by CAP in HaCaT cells 11.39%、51.96%。75.98%. The effects of PF are different on the calcium influx in between HaCaT cells and HEK293T-TRPV1 cells, which suggested that PF was not directly effect calcium influx through the TRPV1 channel.
8. CAP has no significant influence on the production of TNFα. Notoginsenoside R1 and Ginsenoside Rg1 has no significant influence on the TRPV1 activation, calcium influx and signal transfer pass way.
9. The result of TRPV1 stimulated by CAP was shown by proteomic technology to find the unreported proteins related with the function of TRPV1. As a result of MOLDI-TOF MS/MS, Triosephosphate isomerase, enolase 1 variant and KERATIN 14 in HaCaT cells treated with CAP have significant changed. The function and role of these proteins on the inflammation in skin should be investigated further.
引文
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