髓系细胞触发受体-1在单核细胞凋亡中的作用及其机制的研究
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摘要
第一部分脓毒症患者外周血单核细胞髓系细胞触发受体-1表达水平与凋亡的相关性
研究目的：髓系细胞触发受体-1(TREM-1)分子是主要表达于外周血单核细胞和中性粒细胞表面的受体,能够放大Toll样受体(Toll-like receptors, TLRs)和Nod样受体(Nod-like receptors, NLRs)介导的炎症反应,在脓毒症等炎症性疾病发病机理中发挥重要作用。但是TREM-1在脓毒症单核细胞和中性粒细胞凋亡中的作用尚未明确。因此,本部分研究通过检测脓毒症患者外周血单核细胞和中性粒细胞TREM-1的表达水平和细胞凋亡率,分析细胞TREM-1的表达水平和细胞凋亡之间的相关性。
研究方法：
本研究纳入2012年7月1日至2012年9月4日大学附属医院外科ICU新入院脓毒症患者为研究组,排除化疗、艾滋病、激素治疗和器官移植等患者。所有纳入患者在入住重症监护病房(Intensive Care Unit, ICU)24小时内进行APACHE Ⅱ (Acute Physiology and Chronic Health Evaluation Ⅱ)评分和SOFA(Sequential Organ Failure Assessment)评分。所有纳入患者在入住ICU24小时内均抽取全血检测全血中单核细胞和中性粒细胞的凋亡水平；同时将全血中的单核细胞和中性粒细胞分离,检测两种细胞TREM-1的表达水平。分别分析单核细胞和中性粒细胞TREM-1表达水平与其凋亡率的相关性。
研究结果：
本研究共纳入外科ICU中符合脓毒症诊断标准的26例患者。在原发疾病中最常见的为急性腹膜炎(26.9%)和肺炎(26.9%),其他还包括急性化脓性梗阻性胆管炎和急性重症胰腺炎等。其中16例患者细菌培养结果阳性,另外10例患者存在临床感染证据。所有患者的外周血单核细胞都检测到TREM-1表达水平和细胞凋亡率,相关性分析显示单核细胞TREM-1表达水平和单核细胞凋亡率成负相关(r=-0.49,P=0.01)。此外,26例患者中有22例成功检测到中性粒细胞TREM-1表达水平与中性粒细胞凋亡率,4例患者检测失败。中性粒细胞TREM-1表达水平与中性粒细胞凋亡率之间无显著相关性(r=-0.28,P=0.21)。
研究结论：
脓毒症患者外周血单核细胞TREM-1表达水平与单核细胞凋亡率呈负相关,中性粒细胞TREM-1表达水平与中性粒细胞凋亡率无显著相关性。研究结果提示：TREM-1在单核细胞抗凋亡中可能具有重要作用。
第二部分TREM-1在单核细胞凋亡中的作用并初步探讨其分子机制
研究目的：
通过构建携带TREM-1基因的重组腺病毒表达载体,获得高表达TREM-1的单核细胞,进行TREM-1在单核细胞凋亡中的作用及其机制的研究,探讨Erk和PI3K/Akt通路和Bcl-2蛋白家族在该凋亡机制中的作用。研究方法：
构建高表达TREM-1的腺病毒表达载体,感染单核细胞系THP-1细胞,用Western blot和流式细胞术检测TREM-1蛋白的表达水平。以高表达TREM-1的THP-1细胞为研究对象,采用激动性抗体激活TREM-1通路,或同时用100ng/ml脂多糖(lipopolysaccharide, LPS)刺激,随后用星形孢菌素(staurosporine, STS)诱导该细胞凋亡,采用流式细胞术检测细胞凋亡水平。采用化学抑制试验观察细胞外信号调节激酶(extracellular-signal-regulated kinase, Erk)通路和磷脂酰肌醇3激酶(phosphatidylinositol3-kinase, PI3K)/Akt通路对TREM-1分子介导的细胞凋亡的影响。采用Western blot法技术检测Bcl-2蛋白家族在TREM-1分子介导的细胞凋亡中的表达水平变化。
研究结果：
Western-blot和流式细胞术检测证实TREM-1重组腺病毒载体构建成功,能在单核细胞系THP-1细胞中稳定表达。激活TREM-1通路能显著降低STS诱导的THP-1细胞的凋亡率(41.8%vs.63%,p<0.05),且在LPS刺激诱导的THP-1细胞(体外炎症模型)中也得到了相似的结果(33.7%vs.54.3%,p<0.05)。用化学药物抑制细胞外信号调节激酶(extracellular-signal-regulated kinase, Erk)或磷脂酰肌醇3激酶(phosphatidylinositol3-kinase, PI3K)/Akt通路的活化,能够减弱TREM-1对THP-1凋亡的抑制作用(Erk抑制剂：29.8%vs.77.7%, p<0.05; PI3K/Akt抑制剂：29.8%vs.69.3%, p<0.05)。Western blot结果显示TREM-1的激活不仅能显著地提高Bcl-2蛋白家族中抗凋亡蛋白髓样细胞白血病-1(myeloid cell leukemia-1, Mcl-1)的表达,而且还能逆转STS对Mcl-1蛋白的抑制作用(p<0.05)。
研究结论：
本研究证实激活TREM-1对单核细胞具有抗凋亡作用,其机制可能与Erk和Akt信号通路的激活、以及下游抗凋亡蛋白Mcl-1的表达升高有关。
第三部分明确Mcl-1分子在TREM-1介导单核细胞抗凋亡通路中的重要作用
研究目的：
探讨上述研究中发现的髓样细胞白血病-1(myeloid cell leukemia-1, Mcl-1)蛋白在单核细胞TREM-1抗凋亡通路中的确切作用,从而明确单核细胞表面TREM-1分子在细胞凋亡、免疫调控中的重要作用。
研究方法：
以高表达TREM-1的THP-1细胞为研究对象,采用化学抑制剂抑制TREM-1通路的下游分子Erk和Akt,Western blot方法检测Mcl-1蛋白水平的变化。采用激动性TREM-1抗体激活TREM-1受体后,加入特异性抑制Mcl-1蛋白表达的Roscovitine (20μM)与0.6μg/ml STS,流式细胞术观察Mcl-1蛋白抑制后对TREM-1发挥抗凋亡作用的影响。
研究结果：
抑制Erk和/或Akt信号分子均导致Mcl-1蛋白表达显著下降(p<0.05)。20μM Roscovitine处理4小时后,TREM-1-THP-细胞的Mcl-1蛋白表达明显被抑制(p<0.05)。将激活TERM-1通路的TREM-1-THP-1细胞用20μM Roscovitine处理后,TREM-1的抗凋亡作用被抑制(68.1%vs.39.5%,p<0.05)。
研究结论：
本研究证实TREM-1可能是通过激活的Erk和Akt通路上调Mcl-1蛋白发挥抗凋亡作用,Mcl-1蛋白可能是TREM-1抗凋亡通路中的重要分子。
Part1The relationship between triggering receptor expressed on myeloid cells-1and monocyte apoptosis in sepsis
Objective:
Triggering receptor expressed on myeloid cells-1(TREM-1) is a cell surface receptor selectively expressed on myeloid cells, which can amplify pro-inflammatory response initiated by Toll-like receptors and Nod-like receptors, and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1in monocyte fate and the detailed molecular mechanisms evoked by TREM-1are unknown. Thus, the expression levels of TREM-1in monocyte and the magnitude of monocyte apoptosis were measured.
Methods:
From July1st2012, to September4th2012, patients who were newly hospitalized in the surgical Intensive Care Unit in the University Hospitals were screened for eligibility. The diagnosis of sepsis met the criteria recommended by American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference. The Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, and the Sequential Organ Failure Assessment (SOFA) score were recorded. Results of microbiological culture were also recorded. Notable exclusion criteria included:human immunodeficiency virus (HIV) positive, treatment with long-term corticosteroids within6months or short-term corticosteroids within4weeks, chemotherapy or radiation therapy within4weeks, or a history of organ transplantation. Ten milliliters of EDTA-anticoagulation peripheral whole blood were drawn from each patient within24hours after diagnosis of sepsis. Monocytes and neutrophils were isolated and extracted for detection of TREM-1by real-time PCR; meanwhile, the magnitude of apoptosis in monocytes and neutrophils in the septic patients were measured by flow cytometry.
Results:
During the study period, twenty-six patients who were diagnosed as sepsis were enrolled in the study. Among them, peritonitis (26.9%) and pneumonia (26.9%) were the most frequent initial diagnosis for the patients. Other diagnosis included obstructive cholecystitis, severe acute pancreatitis, and so on. Microbiological inspection evidenced that16patients experienced a documented infection. The other10patients showed clinically suspected infections stated by senior intensivists. The expression levels of TREM-1and the magnitude of apoptosis in monocyte were successfully detected in all of the patients. Correlation analysis showed that the expression levels of TREM-1were reversely correlated with the magnitude of apoptosis in monocyte (r=-0.49, P=0.01). In addition, the expression levels of TREM-1and the magnitude of apoptosis in neutrophil were measured in22out of26septic patients. Although the expression levels of TREM-1were not significantly correlated with the magnitude of apoptosis (r=-0.28, P=0.21), a trend that the neutrophil with higher expression levels of TREM-1have less magnitude of apoptosis was observed.
Conclusion:
In septic patients, TREM-1levels were reversely correlated to the magnitude of apoptosis in monocyte. This study demonstrated that TREM-1played an important role in monocyte apoptosis.
Part2The effect and mechanism of TREM-1on monocyte apoptosis
Objective:
To investigate the effect and mechanism of TREM-1on monocyte apoptosis.
Method:
Adenoviruses overexpressing TREM-1were constructed and transfected into monocytic THP-1cells. After activation of TREM-1by agonist antibody with/without lipopolysaccharide, apoptosis was induced by staurosporine and assayed using flow cytometry. The signaling pathways downstream of TREM-1were illustrated by inhibitory experiments. Pro-/anti-apoptotic protein levels were measured using immunoblot.
Results:
Activation of TREM-1protected monocytes from staurosporine induced apoptosis (41.8%vs.63%, p<0.05). This characteristic was also obtained under lipopolysaccharide stimulation (33.7%vs.54.3%, p<0.05), an in vitro inflammatory model. The protection of TREM-1against monocyte apoptosis was abrogated after inhibition of extracellular-signal-regulated kinase (Erk)(77.7%vs.29.8%, p<0.05) or PI3K/Akt (69.3%vs.29.8%, p<0.05) signaling. Western blot analysis showed that cross-linking of TREM-1remarkably upregulated myeloid cell leukemia-1(Mcl-1) protein level and reversed staurosporine-suppressed Mcl-1expression (p<0.05).
Conclusion:
This study demonstrated that activation of TREM-1protected monocytic cells from apoptosis through activation of both Erk and Akt pathways and increased expression of Mcl-1protein.
Part3The importance of myeloid cell leukemia-1in TREM-1mediated protection against apoptosis
Objective:
To illustrate the importance of myeloid cell leukemia-1(Mcl-1) in TREM-1mediated protection against apoptosis.
Method:
The extracellular-signal-regulated kinase (Erk) and/or PI3K/Akt, down stream of TREM-1signaling, were inhibited to detect Mcl-1expression level. Then a cyclin dependent kinase inhibitor, Roscovitine, which could specifically downregulate Mcl-1, was added into the transfected cells simultaneously with STS in a final concentration of20μM.
Results:
Inhibition of Erk or Akt resulted in the reduction of Mcl-1expression (p<0.05). Treatment of the agonist-activated Ad.TREM-1-transfected cells with20μM Roscovitine for4hours did suppress the protein levels of Mcl-1(p<0.05). Roscovitine abrogated the protective effect of TREM-1against apoptosis (68.1%vs.39.5%, p<0.05).
Conclusion:
This study confirming that Mcl-1was a critical molecule accounting for TREM-1mediated signaling pathway against apoptosis.
研究目的：髓系细胞触发受体-1(TREM-1)分子是主要表达于外周血单核细胞和中性粒细胞表面的受体,能够放大Toll样受体(Toll-like receptors, TLRs)和Nod样受体(Nod-like receptors, NLRs)介导的炎症反应,在脓毒症等炎症性疾病发病机理中发挥重要作用。但是TREM-1在脓毒症单核细胞和中性粒细胞凋亡中的作用尚未明确。因此,本部分研究通过检测脓毒症患者外周血单核细胞和中性粒细胞TREM-1的表达水平和细胞凋亡率,分析细胞TREM-1的表达水平和细胞凋亡之间的相关性。
研究方法：
本研究纳入2012年7月1日至2012年9月4日大学附属医院外科ICU新入院脓毒症患者为研究组,排除化疗、艾滋病、激素治疗和器官移植等患者。所有纳入患者在入住重症监护病房(Intensive Care Unit, ICU)24小时内进行APACHE Ⅱ (Acute Physiology and Chronic Health Evaluation Ⅱ)评分和SOFA(Sequential Organ Failure Assessment)评分。所有纳入患者在入住ICU24小时内均抽取全血检测全血中单核细胞和中性粒细胞的凋亡水平；同时将全血中的单核细胞和中性粒细胞分离,检测两种细胞TREM-1的表达水平。分别分析单核细胞和中性粒细胞TREM-1表达水平与其凋亡率的相关性。
研究结果：
本研究共纳入外科ICU中符合脓毒症诊断标准的26例患者。在原发疾病中最常见的为急性腹膜炎(26.9%)和肺炎(26.9%),其他还包括急性化脓性梗阻性胆管炎和急性重症胰腺炎等。其中16例患者细菌培养结果阳性,另外10例患者存在临床感染证据。所有患者的外周血单核细胞都检测到TREM-1表达水平和细胞凋亡率,相关性分析显示单核细胞TREM-1表达水平和单核细胞凋亡率成负相关(r=-0.49,P=0.01)。此外,26例患者中有22例成功检测到中性粒细胞TREM-1表达水平与中性粒细胞凋亡率,4例患者检测失败。中性粒细胞TREM-1表达水平与中性粒细胞凋亡率之间无显著相关性(r=-0.28,P=0.21)。
研究结论：
脓毒症患者外周血单核细胞TREM-1表达水平与单核细胞凋亡率呈负相关,中性粒细胞TREM-1表达水平与中性粒细胞凋亡率无显著相关性。研究结果提示：TREM-1在单核细胞抗凋亡中可能具有重要作用。
第二部分TREM-1在单核细胞凋亡中的作用并初步探讨其分子机制
研究目的：
通过构建携带TREM-1基因的重组腺病毒表达载体,获得高表达TREM-1的单核细胞,进行TREM-1在单核细胞凋亡中的作用及其机制的研究,探讨Erk和PI3K/Akt通路和Bcl-2蛋白家族在该凋亡机制中的作用。研究方法：
构建高表达TREM-1的腺病毒表达载体,感染单核细胞系THP-1细胞,用Western blot和流式细胞术检测TREM-1蛋白的表达水平。以高表达TREM-1的THP-1细胞为研究对象,采用激动性抗体激活TREM-1通路,或同时用100ng/ml脂多糖(lipopolysaccharide, LPS)刺激,随后用星形孢菌素(staurosporine, STS)诱导该细胞凋亡,采用流式细胞术检测细胞凋亡水平。采用化学抑制试验观察细胞外信号调节激酶(extracellular-signal-regulated kinase, Erk)通路和磷脂酰肌醇3激酶(phosphatidylinositol3-kinase, PI3K)/Akt通路对TREM-1分子介导的细胞凋亡的影响。采用Western blot法技术检测Bcl-2蛋白家族在TREM-1分子介导的细胞凋亡中的表达水平变化。
研究结果：
Western-blot和流式细胞术检测证实TREM-1重组腺病毒载体构建成功,能在单核细胞系THP-1细胞中稳定表达。激活TREM-1通路能显著降低STS诱导的THP-1细胞的凋亡率(41.8%vs.63%,p<0.05),且在LPS刺激诱导的THP-1细胞(体外炎症模型)中也得到了相似的结果(33.7%vs.54.3%,p<0.05)。用化学药物抑制细胞外信号调节激酶(extracellular-signal-regulated kinase, Erk)或磷脂酰肌醇3激酶(phosphatidylinositol3-kinase, PI3K)/Akt通路的活化,能够减弱TREM-1对THP-1凋亡的抑制作用(Erk抑制剂：29.8%vs.77.7%, p<0.05; PI3K/Akt抑制剂：29.8%vs.69.3%, p<0.05)。Western blot结果显示TREM-1的激活不仅能显著地提高Bcl-2蛋白家族中抗凋亡蛋白髓样细胞白血病-1(myeloid cell leukemia-1, Mcl-1)的表达,而且还能逆转STS对Mcl-1蛋白的抑制作用(p<0.05)。
研究结论：
本研究证实激活TREM-1对单核细胞具有抗凋亡作用,其机制可能与Erk和Akt信号通路的激活、以及下游抗凋亡蛋白Mcl-1的表达升高有关。
第三部分明确Mcl-1分子在TREM-1介导单核细胞抗凋亡通路中的重要作用
研究目的：
探讨上述研究中发现的髓样细胞白血病-1(myeloid cell leukemia-1, Mcl-1)蛋白在单核细胞TREM-1抗凋亡通路中的确切作用,从而明确单核细胞表面TREM-1分子在细胞凋亡、免疫调控中的重要作用。
研究方法：
以高表达TREM-1的THP-1细胞为研究对象,采用化学抑制剂抑制TREM-1通路的下游分子Erk和Akt,Western blot方法检测Mcl-1蛋白水平的变化。采用激动性TREM-1抗体激活TREM-1受体后,加入特异性抑制Mcl-1蛋白表达的Roscovitine (20μM)与0.6μg/ml STS,流式细胞术观察Mcl-1蛋白抑制后对TREM-1发挥抗凋亡作用的影响。
研究结果：
抑制Erk和/或Akt信号分子均导致Mcl-1蛋白表达显著下降(p<0.05)。20μM Roscovitine处理4小时后,TREM-1-THP-细胞的Mcl-1蛋白表达明显被抑制(p<0.05)。将激活TERM-1通路的TREM-1-THP-1细胞用20μM Roscovitine处理后,TREM-1的抗凋亡作用被抑制(68.1%vs.39.5%,p<0.05)。
研究结论：
本研究证实TREM-1可能是通过激活的Erk和Akt通路上调Mcl-1蛋白发挥抗凋亡作用,Mcl-1蛋白可能是TREM-1抗凋亡通路中的重要分子。
Part1The relationship between triggering receptor expressed on myeloid cells-1and monocyte apoptosis in sepsis
Objective:
Triggering receptor expressed on myeloid cells-1(TREM-1) is a cell surface receptor selectively expressed on myeloid cells, which can amplify pro-inflammatory response initiated by Toll-like receptors and Nod-like receptors, and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1in monocyte fate and the detailed molecular mechanisms evoked by TREM-1are unknown. Thus, the expression levels of TREM-1in monocyte and the magnitude of monocyte apoptosis were measured.
Methods:
From July1st2012, to September4th2012, patients who were newly hospitalized in the surgical Intensive Care Unit in the University Hospitals were screened for eligibility. The diagnosis of sepsis met the criteria recommended by American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference. The Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, and the Sequential Organ Failure Assessment (SOFA) score were recorded. Results of microbiological culture were also recorded. Notable exclusion criteria included:human immunodeficiency virus (HIV) positive, treatment with long-term corticosteroids within6months or short-term corticosteroids within4weeks, chemotherapy or radiation therapy within4weeks, or a history of organ transplantation. Ten milliliters of EDTA-anticoagulation peripheral whole blood were drawn from each patient within24hours after diagnosis of sepsis. Monocytes and neutrophils were isolated and extracted for detection of TREM-1by real-time PCR; meanwhile, the magnitude of apoptosis in monocytes and neutrophils in the septic patients were measured by flow cytometry.
Results:
During the study period, twenty-six patients who were diagnosed as sepsis were enrolled in the study. Among them, peritonitis (26.9%) and pneumonia (26.9%) were the most frequent initial diagnosis for the patients. Other diagnosis included obstructive cholecystitis, severe acute pancreatitis, and so on. Microbiological inspection evidenced that16patients experienced a documented infection. The other10patients showed clinically suspected infections stated by senior intensivists. The expression levels of TREM-1and the magnitude of apoptosis in monocyte were successfully detected in all of the patients. Correlation analysis showed that the expression levels of TREM-1were reversely correlated with the magnitude of apoptosis in monocyte (r=-0.49, P=0.01). In addition, the expression levels of TREM-1and the magnitude of apoptosis in neutrophil were measured in22out of26septic patients. Although the expression levels of TREM-1were not significantly correlated with the magnitude of apoptosis (r=-0.28, P=0.21), a trend that the neutrophil with higher expression levels of TREM-1have less magnitude of apoptosis was observed.
Conclusion:
In septic patients, TREM-1levels were reversely correlated to the magnitude of apoptosis in monocyte. This study demonstrated that TREM-1played an important role in monocyte apoptosis.
Part2The effect and mechanism of TREM-1on monocyte apoptosis
Objective:
To investigate the effect and mechanism of TREM-1on monocyte apoptosis.
Method:
Adenoviruses overexpressing TREM-1were constructed and transfected into monocytic THP-1cells. After activation of TREM-1by agonist antibody with/without lipopolysaccharide, apoptosis was induced by staurosporine and assayed using flow cytometry. The signaling pathways downstream of TREM-1were illustrated by inhibitory experiments. Pro-/anti-apoptotic protein levels were measured using immunoblot.
Results:
Activation of TREM-1protected monocytes from staurosporine induced apoptosis (41.8%vs.63%, p<0.05). This characteristic was also obtained under lipopolysaccharide stimulation (33.7%vs.54.3%, p<0.05), an in vitro inflammatory model. The protection of TREM-1against monocyte apoptosis was abrogated after inhibition of extracellular-signal-regulated kinase (Erk)(77.7%vs.29.8%, p<0.05) or PI3K/Akt (69.3%vs.29.8%, p<0.05) signaling. Western blot analysis showed that cross-linking of TREM-1remarkably upregulated myeloid cell leukemia-1(Mcl-1) protein level and reversed staurosporine-suppressed Mcl-1expression (p<0.05).
Conclusion:
This study demonstrated that activation of TREM-1protected monocytic cells from apoptosis through activation of both Erk and Akt pathways and increased expression of Mcl-1protein.
Part3The importance of myeloid cell leukemia-1in TREM-1mediated protection against apoptosis
Objective:
To illustrate the importance of myeloid cell leukemia-1(Mcl-1) in TREM-1mediated protection against apoptosis.
Method:
The extracellular-signal-regulated kinase (Erk) and/or PI3K/Akt, down stream of TREM-1signaling, were inhibited to detect Mcl-1expression level. Then a cyclin dependent kinase inhibitor, Roscovitine, which could specifically downregulate Mcl-1, was added into the transfected cells simultaneously with STS in a final concentration of20μM.
Results:
Inhibition of Erk or Akt resulted in the reduction of Mcl-1expression (p<0.05). Treatment of the agonist-activated Ad.TREM-1-transfected cells with20μM Roscovitine for4hours did suppress the protein levels of Mcl-1(p<0.05). Roscovitine abrogated the protective effect of TREM-1against apoptosis (68.1%vs.39.5%, p<0.05).
Conclusion:
This study confirming that Mcl-1was a critical molecule accounting for TREM-1mediated signaling pathway against apoptosis.
引文
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[6]Dai Y, Rahmani M, Pei XY. Farnesyltransferase inhibitors interact synergistically with the Chkl inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. Blood 2005;105:1706-1716
[7]Westphal D, Dewson G, Czabotar PE, et al. Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 2011; 1813:521-531
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