N-（1-苯乙基）-3-（2-呋喃基）丙烯酰胺对巨噬细胞分泌细胞因子的影响
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摘要
炎症反应是具有血管系统的活体组织对各种损伤因子的刺激所发生的一种防御机制,适当的炎症反应有利于激活免疫系统清除病原体,并可促进组织愈合；反应不足导致免疫缺陷,这可能引起感染和癌症；反应过度会增加多种疾病的发病率和死亡率,如类风湿性关节炎、结节性肠炎等。
脂多糖(1 ipopolysaccharide,LPS)作为革兰阴性细菌的细胞壁成分,可以刺激巨噬细胞、内皮细胞等产生一系列致炎因子如肿瘤坏死因子-(TNF-α)、白细胞介素-1(IL-1)、IL-6、IL-8等表达。大量实验表明,在LPS所致的炎症因子表达中,细胞内的一些信号通路如MAPK(mitogen-activated protein kinase)通路,NF-κB通路起重要作用。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是生物体内重要的信号转导系统之一,参与介导细胞生长、分裂、分化、死亡以及细胞间的功能同步等多种生理过程。在细胞内以MAPKKK/MAPKK /MAPK为主干,再加上各种上游影响因子和下游作用底物,构成了一个功能多样、反应灵敏的信号转导网络。这些与细胞信号相关的酶把细胞外信号从细胞表面传递到细胞核,导致基因表达发生变化。而p38是MAPK通路中重要成员之一,与TNF-α、IL-1等致炎因子的诱生关系密切。研究发现,NF-κB是LPS介导的信号转导通路中最重要的下游通路,在多种炎症介质的表达调控中均具有重要作用。NF-κB的激活涉及IKB(NF-κB抑制剂)的磷酸化,而后者有赖于IKK(IκB激酶)的调控,IKK/IκB/NF-κB是一个有机联系的系统,该信号通路在机体发挥重要作用[17-20]。
体液因素或细胞因子的自分泌和旁分泌影响抗炎或炎性介质释放,神经及其递质也有直接调节作用。2000年,Nature杂志报道乙酰胆碱(acetylcholine, ACh)与巨噬细胞上尼古丁受体结合能够抑制内毒素诱导的炎性因子TNF-α, IL-1β, IL-6, IL-18等分泌。进一步研究发现乙酰胆碱的作用主要是通过与巨噬细胞上的α7烟碱型乙酰胆碱(α7-nAChR)受体结合,通过细胞内一系列的信号传递,最终抑制了Jak2-STAT3和NF-κB信号的激活,从而抑制了炎性因子的产生。由于乙酰胆碱是迷走神经末梢分泌的主要神经递质,他们把这条通路命名为“胆碱能抗炎通路’'(cholinergic anti-inflammatory pathway, CAP)。有研究表明α7-nAChR在该通路中起关键作用,它被激活后明显抑制免疫细胞产生炎性因子如TNFα、IL-12、高迁移率族蛋白1 (high-mobility group box1,HMGB1)等,这些是α7nAChR介导抗炎作用的主要机制,与此同时它还可以促进转化生长因子β(transforming growth factorβ,TGFβ)、IL-10等抗炎因子的产生。因此,对α7nAChR的激动剂的研究可为新型抗炎药物的开发提供可能性。本文所涉及的化合物GX-50则通过生物信息学计算发现一种潜在的α7nAChR激动剂,而N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺是将GX-50进行部分化学修饰所得,我们希望能通过相关实验对这种化合物进行研究,为找到一种新型的抗炎药物奠定基础。
本研究的目的就是想探讨N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺对于巨噬细胞Ana-1分泌细胞因子TNF-α和IL-1的影响,并进一步研究其作用机制。实验首先用不同浓度的N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺处理巨噬细胞Ana-1,用MTT和LDH的方法进行药物毒性检测,筛选出对细胞无毒的1μM的N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺浓度用于后续实验。接下来分别设计control(只加1640培养基)组,只加N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺组,先用1μM的N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺浓度预处理Ana-130分钟,再加入LPS刺激4小时组,只加LPS处理4小时组共4组实验。分别收集上清和细胞,提取蛋白质和RNA用于ELISA和PCR方法检测各组TNF-α和IL-1的基因表达量,Western检测IKK,IκB,p38的磷酸化蛋白量以及EMSA的方法检测NF-κB的活化程度。最后用受体结合实验检测N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺与α7烟碱型乙酰胆碱受体的结合能力。
结果显示,N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺对LPS刺激的巨噬细胞的细胞因子TNF-α分泌有显著的抑制作用,其分泌量约比未经化合物A预处理的分泌量的下降了50%左右,对IL-1分泌的抑制作用不明显。在P38MAPK通路中和在NF-κB通路中,N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺预处理再用LPS处理组比只用LPS处理组p38和IKK、IκB的蛋白磷酸化程度分别下降了约29.8%,约27.7%和约58.8%。EMSA结果也表明,N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺预处理再用LPS刺激组比只用LPS刺激组NF-κB活化程度明显下降。而α7nAChR受体特异性结合实验也表明N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺可能是α7nAChR的潜在激动剂。
通过本次实验证明了N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺对巨噬细胞分泌的炎性因子TNF-α有显著抑制作用,其机制可能主要通过抑制了LPS刺激的P38MAPK和NF-κB信号通路活化起到抗炎作用。而N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺α7nAChR良好的结合,也暗示了胆碱能抗炎通路可能也参与其中,但是其深入机制还需要进行进一步研究。
Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, The magnitude of the inflammatory response is crucial and insufficient responses result in immunodeficiency, which can lead to infection and cancer. Excessive responses cause morbidity and mortality in diseases such as rheumatoid arthritis, and cerebral and myocardial ischaemia. If inflammation spreads into the bloodstream, as occurs in septic shock syndrome, sepsis, meningitis and severe trauma, the inflammatory responses can be more dangerous than the original inciting stimulus.
Lipopolysaccharide (lipopolysaccharide, LPS) can stimulate macrophages and endothelial cells realease a series of proinflammatory cytokines such as tumor necrosis factor-(TNF-α), interleukin-1 (IL-1), IL-6, IL-8 expression, etc.A large number of experiments show that the MAPK (mitogen-activated protein kinase) pathway, NF-κB pathway plays an important role in LPS-induced expression of inflammatory cytokines. Mitogen-activated protein kinase (mitogen-activated protein kinase, MAPK) are important in vivo signal transduction systems in the world, involved in mediating cell growth, division, differentiation, death and the function of cell synchronization, and other physiological processes. In vivo, MAPKKK/ MAPKK/MAPK is a backbone, plus a variety of upstream and downstream factors and substrate, forming a versatile, responsive signal transduction network. These cell signaling enzymes can delivere extracellular signals to the nucleus from the surface, resulting in changes in gene expressions. The p38 is an important member of the MAPK pathway, with close connection of TNF-α, IL-1 and other inflammatory factors. NF-κB pathway is downstream in LPS signal transduction. NF-κB pathway plays an important role in the regulation of expression of various inflammatory mediators.NF-κB activates involving IKB (NF-κB inhibitor) phosphorylation, which depends on IKK (IκB kinase). IKK/IκB/NF-κB are an organic system, playing important role on the signal transduction pathway in the body.
Humoral factors or cytokines in autocrine and paracrine mediators have the anti-inflammatory or inflammatory effects and neurotransmitters also regulate inflammation directly. In 2000, Nature reported that acetylcholine (ACh) can bind to nicotine receptors on macrophages so that endotoxin-induced inflammatory factor TNF-α, IL-1β, IL-6, IL-18 secretion were inhibited. Further studies revealed that acetylcholine mainly binded with a7 nicotinic acetylcholine (a7-nAChR) receptor, through a series of intracellular signaling, ultimately inhibited Jak2-STAT3 and NF-κB signal activation, thus inhibiting the production of inflammatory factors. This pathway is named cholinergic anti-inflammatory pathway (CAP). Studies show that a7-nAChR plays a key role in this pathway, after it is activated, it inhibits the secretion of inflammatory factors such as TNF alpha, IL-12, high mobility boxl group (HMGB1), meanwhile it can also promote transforming growth factor beta (TGF beta), IL-10 etc anti-inflammatory factor. Thus, the studies on a7-nAChR receptor agonists provide the possibilities for the new anti-inflammatory drugs. The GX-50 compound involved in this passage is a potential alpha 7nAChR agonist found by bioinformatics calculation, and the 3-(2-furanyl)-N-(1-phenylethyl) acrylamide is partially modified from GX-50, we hope to find a new compound from this 3-(2-furanyl)-N-(1-phenylethyl) acrylamide which can inhibit the secretion of inflammatory factors and then have anti-inflammatory effect by several experiments evidences.
The purpose of this study is to investigate the direct and indireact effect of 3-(2-furanyl)-N-(1-phenylethyl) acrylamide on expressions of TNF-αand IL-1 in macrophages Ana-1 and analysis the pathways on the mechanisms.
Firstly, the toxicities of the 3-(2-furanyl)-N-(1-phenylethyl) acrylamide are tested by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay and LDH (lactate dehydrogenase). Then the best concentration-1μM of 3-(2-furanyl)-N-(1-phenylethyl) acrylamide is found for the further study. Next,4 groups was established as following:control (only 1640 medium plus), analogues, LPS, analogues pretreated for 30 min and then LPS treated for 4h. The supernants and cells were collected and used for RNA and protein extractions. ELISA (enzyme linked immunosorbent assay) and PCR were used to detect the contents of TNF-alpha and IL-1 which are significant media in local and whole inflammatory response. Western blot experiment was used to measure the phosphorylation of IKK, IκB and p38. The influence on the NF-κB pathway was detected by EMSA.
The results show that the level of expressions of TNF-alpha were significantly decreased of in the groups of analogues pretreated by about 50% respectively of LPS-treated group and there was no significant influence on expression of IL-1. The phosphorylation levels of p38 of the P38MAPK pathway and IKK、IκB of NF-κB pathway were inhibited to about 29.8%, 27.7% and 58.8%.3-(2-furanyl)-N-(1-phenylethyl) acrylamide also inhibited the activation of NF-KB pathway. In addition, our research revealed that 3-(2-furanyl)-N-(1-phenylethyl) acrylamide was a potential a7 nAChR agonist.
In a word, with the efforts I sucessefully find 3-(2-furanyl)-N-(1-phenylethyl) acrylamide has obvious effect on the inhibition of TNF-αby inhibiting the activation of P38MAPK pathway and NF-KB pathway. In addition, further research was needed to investigate anti-inflammatory pathway with the anti-inflammatory effect of 3-(2-furanyl)-N-(1-phenylethyl) acrylamide for knowing 3-(2-furanyl)-N-(1-phenylethyl) acrylamide was a potential a7 nAChR agonist.
脂多糖(1 ipopolysaccharide,LPS)作为革兰阴性细菌的细胞壁成分,可以刺激巨噬细胞、内皮细胞等产生一系列致炎因子如肿瘤坏死因子-(TNF-α)、白细胞介素-1(IL-1)、IL-6、IL-8等表达。大量实验表明,在LPS所致的炎症因子表达中,细胞内的一些信号通路如MAPK(mitogen-activated protein kinase)通路,NF-κB通路起重要作用。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是生物体内重要的信号转导系统之一,参与介导细胞生长、分裂、分化、死亡以及细胞间的功能同步等多种生理过程。在细胞内以MAPKKK/MAPKK /MAPK为主干,再加上各种上游影响因子和下游作用底物,构成了一个功能多样、反应灵敏的信号转导网络。这些与细胞信号相关的酶把细胞外信号从细胞表面传递到细胞核,导致基因表达发生变化。而p38是MAPK通路中重要成员之一,与TNF-α、IL-1等致炎因子的诱生关系密切。研究发现,NF-κB是LPS介导的信号转导通路中最重要的下游通路,在多种炎症介质的表达调控中均具有重要作用。NF-κB的激活涉及IKB(NF-κB抑制剂)的磷酸化,而后者有赖于IKK(IκB激酶)的调控,IKK/IκB/NF-κB是一个有机联系的系统,该信号通路在机体发挥重要作用[17-20]。
体液因素或细胞因子的自分泌和旁分泌影响抗炎或炎性介质释放,神经及其递质也有直接调节作用。2000年,Nature杂志报道乙酰胆碱(acetylcholine, ACh)与巨噬细胞上尼古丁受体结合能够抑制内毒素诱导的炎性因子TNF-α, IL-1β, IL-6, IL-18等分泌。进一步研究发现乙酰胆碱的作用主要是通过与巨噬细胞上的α7烟碱型乙酰胆碱(α7-nAChR)受体结合,通过细胞内一系列的信号传递,最终抑制了Jak2-STAT3和NF-κB信号的激活,从而抑制了炎性因子的产生。由于乙酰胆碱是迷走神经末梢分泌的主要神经递质,他们把这条通路命名为“胆碱能抗炎通路’'(cholinergic anti-inflammatory pathway, CAP)。有研究表明α7-nAChR在该通路中起关键作用,它被激活后明显抑制免疫细胞产生炎性因子如TNFα、IL-12、高迁移率族蛋白1 (high-mobility group box1,HMGB1)等,这些是α7nAChR介导抗炎作用的主要机制,与此同时它还可以促进转化生长因子β(transforming growth factorβ,TGFβ)、IL-10等抗炎因子的产生。因此,对α7nAChR的激动剂的研究可为新型抗炎药物的开发提供可能性。本文所涉及的化合物GX-50则通过生物信息学计算发现一种潜在的α7nAChR激动剂,而N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺是将GX-50进行部分化学修饰所得,我们希望能通过相关实验对这种化合物进行研究,为找到一种新型的抗炎药物奠定基础。
本研究的目的就是想探讨N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺对于巨噬细胞Ana-1分泌细胞因子TNF-α和IL-1的影响,并进一步研究其作用机制。实验首先用不同浓度的N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺处理巨噬细胞Ana-1,用MTT和LDH的方法进行药物毒性检测,筛选出对细胞无毒的1μM的N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺浓度用于后续实验。接下来分别设计control(只加1640培养基)组,只加N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺组,先用1μM的N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺浓度预处理Ana-130分钟,再加入LPS刺激4小时组,只加LPS处理4小时组共4组实验。分别收集上清和细胞,提取蛋白质和RNA用于ELISA和PCR方法检测各组TNF-α和IL-1的基因表达量,Western检测IKK,IκB,p38的磷酸化蛋白量以及EMSA的方法检测NF-κB的活化程度。最后用受体结合实验检测N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺与α7烟碱型乙酰胆碱受体的结合能力。
结果显示,N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺对LPS刺激的巨噬细胞的细胞因子TNF-α分泌有显著的抑制作用,其分泌量约比未经化合物A预处理的分泌量的下降了50%左右,对IL-1分泌的抑制作用不明显。在P38MAPK通路中和在NF-κB通路中,N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺预处理再用LPS处理组比只用LPS处理组p38和IKK、IκB的蛋白磷酸化程度分别下降了约29.8%,约27.7%和约58.8%。EMSA结果也表明,N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺预处理再用LPS刺激组比只用LPS刺激组NF-κB活化程度明显下降。而α7nAChR受体特异性结合实验也表明N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺可能是α7nAChR的潜在激动剂。
通过本次实验证明了N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺对巨噬细胞分泌的炎性因子TNF-α有显著抑制作用,其机制可能主要通过抑制了LPS刺激的P38MAPK和NF-κB信号通路活化起到抗炎作用。而N-(1-苯乙基)-3-(2-呋喃基)丙烯酰胺α7nAChR良好的结合,也暗示了胆碱能抗炎通路可能也参与其中,但是其深入机制还需要进行进一步研究。
Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, The magnitude of the inflammatory response is crucial and insufficient responses result in immunodeficiency, which can lead to infection and cancer. Excessive responses cause morbidity and mortality in diseases such as rheumatoid arthritis, and cerebral and myocardial ischaemia. If inflammation spreads into the bloodstream, as occurs in septic shock syndrome, sepsis, meningitis and severe trauma, the inflammatory responses can be more dangerous than the original inciting stimulus.
Lipopolysaccharide (lipopolysaccharide, LPS) can stimulate macrophages and endothelial cells realease a series of proinflammatory cytokines such as tumor necrosis factor-(TNF-α), interleukin-1 (IL-1), IL-6, IL-8 expression, etc.A large number of experiments show that the MAPK (mitogen-activated protein kinase) pathway, NF-κB pathway plays an important role in LPS-induced expression of inflammatory cytokines. Mitogen-activated protein kinase (mitogen-activated protein kinase, MAPK) are important in vivo signal transduction systems in the world, involved in mediating cell growth, division, differentiation, death and the function of cell synchronization, and other physiological processes. In vivo, MAPKKK/ MAPKK/MAPK is a backbone, plus a variety of upstream and downstream factors and substrate, forming a versatile, responsive signal transduction network. These cell signaling enzymes can delivere extracellular signals to the nucleus from the surface, resulting in changes in gene expressions. The p38 is an important member of the MAPK pathway, with close connection of TNF-α, IL-1 and other inflammatory factors. NF-κB pathway is downstream in LPS signal transduction. NF-κB pathway plays an important role in the regulation of expression of various inflammatory mediators.NF-κB activates involving IKB (NF-κB inhibitor) phosphorylation, which depends on IKK (IκB kinase). IKK/IκB/NF-κB are an organic system, playing important role on the signal transduction pathway in the body.
Humoral factors or cytokines in autocrine and paracrine mediators have the anti-inflammatory or inflammatory effects and neurotransmitters also regulate inflammation directly. In 2000, Nature reported that acetylcholine (ACh) can bind to nicotine receptors on macrophages so that endotoxin-induced inflammatory factor TNF-α, IL-1β, IL-6, IL-18 secretion were inhibited. Further studies revealed that acetylcholine mainly binded with a7 nicotinic acetylcholine (a7-nAChR) receptor, through a series of intracellular signaling, ultimately inhibited Jak2-STAT3 and NF-κB signal activation, thus inhibiting the production of inflammatory factors. This pathway is named cholinergic anti-inflammatory pathway (CAP). Studies show that a7-nAChR plays a key role in this pathway, after it is activated, it inhibits the secretion of inflammatory factors such as TNF alpha, IL-12, high mobility boxl group (HMGB1), meanwhile it can also promote transforming growth factor beta (TGF beta), IL-10 etc anti-inflammatory factor. Thus, the studies on a7-nAChR receptor agonists provide the possibilities for the new anti-inflammatory drugs. The GX-50 compound involved in this passage is a potential alpha 7nAChR agonist found by bioinformatics calculation, and the 3-(2-furanyl)-N-(1-phenylethyl) acrylamide is partially modified from GX-50, we hope to find a new compound from this 3-(2-furanyl)-N-(1-phenylethyl) acrylamide which can inhibit the secretion of inflammatory factors and then have anti-inflammatory effect by several experiments evidences.
The purpose of this study is to investigate the direct and indireact effect of 3-(2-furanyl)-N-(1-phenylethyl) acrylamide on expressions of TNF-αand IL-1 in macrophages Ana-1 and analysis the pathways on the mechanisms.
Firstly, the toxicities of the 3-(2-furanyl)-N-(1-phenylethyl) acrylamide are tested by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay and LDH (lactate dehydrogenase). Then the best concentration-1μM of 3-(2-furanyl)-N-(1-phenylethyl) acrylamide is found for the further study. Next,4 groups was established as following:control (only 1640 medium plus), analogues, LPS, analogues pretreated for 30 min and then LPS treated for 4h. The supernants and cells were collected and used for RNA and protein extractions. ELISA (enzyme linked immunosorbent assay) and PCR were used to detect the contents of TNF-alpha and IL-1 which are significant media in local and whole inflammatory response. Western blot experiment was used to measure the phosphorylation of IKK, IκB and p38. The influence on the NF-κB pathway was detected by EMSA.
The results show that the level of expressions of TNF-alpha were significantly decreased of in the groups of analogues pretreated by about 50% respectively of LPS-treated group and there was no significant influence on expression of IL-1. The phosphorylation levels of p38 of the P38MAPK pathway and IKK、IκB of NF-κB pathway were inhibited to about 29.8%, 27.7% and 58.8%.3-(2-furanyl)-N-(1-phenylethyl) acrylamide also inhibited the activation of NF-KB pathway. In addition, our research revealed that 3-(2-furanyl)-N-(1-phenylethyl) acrylamide was a potential a7 nAChR agonist.
In a word, with the efforts I sucessefully find 3-(2-furanyl)-N-(1-phenylethyl) acrylamide has obvious effect on the inhibition of TNF-αby inhibiting the activation of P38MAPK pathway and NF-KB pathway. In addition, further research was needed to investigate anti-inflammatory pathway with the anti-inflammatory effect of 3-(2-furanyl)-N-(1-phenylethyl) acrylamide for knowing 3-(2-furanyl)-N-(1-phenylethyl) acrylamide was a potential a7 nAChR agonist.
引文
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