激活素调控小鼠巨噬细胞活性的信号传导机制研究
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摘要
激活素(Activin)属于TGFβ超家族成员,在神经细胞分化诱导、造血细胞增殖和分化、内分泌中枢垂体性激素分泌调节等多方面发挥重要作用,同时激活素还是组织修复、再生和分化的重要调节因子,参与机体炎症和急性期反应。巨噬细胞是参与机体炎性应答的主要细胞,前期研究发现激活素可以调控巨噬细胞分泌NO,其作用与巨噬细胞活化状态有关。本研究进一步探讨激活素对巨噬细胞活性的调节作用及其可能的信号传导机制。
巨噬细胞不仅具有分泌细胞因子、NO等作用,还是重要的吞噬细胞。因此,本研究采用原代培养C57BL/6小鼠腹腔巨噬细胞、传代培养BALB/c小鼠巨噬细胞系RAW264.7细胞为实验对象,通过分析IL-1β、NO的分泌、IL-1β、iNOS mRNA表达及细胞吞噬活性,系统探讨激活素A对巨噬细胞活性的双向调控作用。实验表明,激活素A刺激小鼠巨噬细胞炎性因子产生、增强吞噬活性,具有剂量依赖关系;而对LPS活化小鼠巨噬细胞的活性具有明显抑制作用。提示激活素对巨噬细胞的分泌活性和吞噬活性,均具有双向调节作用,此作用与巨噬细胞的激活状态有关。其作用有助于维持机体生理平衡,防止因炎症反应过度而造成的损害。
激活素对细胞的作用具有明显的组织学特异性,其作用的特异性与其受体后信号传导差异有关,前期研究表明巨噬细胞高表达激活素Ⅱ型受体(ActRⅡA)。围绕ActRⅡA信号传导途径的研究,发现了新的信号调控蛋白——激活素受体相互作用蛋白(ActRIP),为明确ActRIPs参与巨噬细胞活性调控的信号传导机制。实验采用基因过表达技术,将ActRIP2、3导入小鼠巨噬细胞,结果显示,ActRIP2抑制小鼠巨噬细胞NO的分泌及iNOS、IL-1 mRNA表达,而ActRIP3促进NO的分泌及iNOS、IL-1 mRNA表达。激活素刺激小鼠巨噬细胞
Activin is synthesized in multiple tissues, and effect on multiple tissues as autocrine and paracrine factors. Abnormal expression of activin was found in patients of inflammatory disease such as hepatic fibrosis, pulmonary fibrosis, arthritis and meningitis etc. Recently more and more evidence indicated that activin relates with inflammation and acute phase reaction closely.1、Activin A enhance the activities of mouse macrophagesMacrophages are the main cells that participate in inflammatory reaction. It is not only the cell secreting cytokines and NO, but also the significant phagocytes. In order to clarified the effect of activin on macrophages which participate inflammatory reaction, firstly, we observed the activity of primary-cultured peritoneal macrophage stimulated by Activin A in C57/BL mouse and that in RAW264.7 cells line of BALB/c mouse.The results showed that activin enhanced the secretion of IL-1β and NO and expression of IL-1β mRNA and iNOS mRNA in primary-cultured macrophages of mouse in a dose-dependent manner. Activin also enhanced the secretion of IL-1β and NO and expression of IL-1β mRNA and iNOS mRNA in RAW264.7 cells line of BALB/c mouse. These data suggest that activin stimulates the production and secretion of IL-1β and NO in the transcription level.
In addition, activin A enhanced the phagocytosis in the wild mouse macrophages and RAW264.7 cells. These results suggest that activin A enhances the activities of mouse macrophage such as the secretion of inflammatory factor and phagocytosis in macrophages.2-. Activin A regulating the inflammation reaction by suppressing the activities of mouse macrophages stimulated by LPSMacrophages are not only the important antigen presentation cells, but also the effective cells in inflammation. In order to clarify the mechanism of activin in inflammation, the effect of activin A on activity of LPS-activated macrophage was observed in this study. The results showed that LPS increase the secretion of IL-1 P and NO, and the expression of IL-1 P and iNOS mRNA, and enhanced phagocytosis of mouse macrophages. Activin of physiological concentration inhibited the secretion of inflammatory factor and phagocytosis of mouse macrophages stimulated by LPS in a dose-dependent manner. This result suggests that activin suppress the activity of macrophage stimulated by LPS.Activin enhances the activity of mouse peritoneal macrophages, and inhibits the production of inflammatory and phagocytosis of LPS-activated macrophages. It suggests that activin shows the function of two-ways in regulating the activity of macrophage. The manner of regulation is related with the inflammation state. And this is help for keeping physiologic equilibrium of organism, and preventing the damage caused by over-response to inflammation. The elucidation of correlation mechanism will provide some new idea to explore the treatment in disease of inflammation.3% The study of relationship between Activin IIA and macrophage
activationThe receptor of .activin is widely expressed in the cells of gonad gland and other tissue out of gonad gland. It is the necessary receptor molecule in keeping growth and differentiation of cells. In activin signal transduction pathways, activin firstly binds to the type II receptor, and type II receptor lead to phosphorylation of the type I receptor. Then, the type I receptor interacts with intracellular signaling molecules, and transfer the signaling into nucleus. As type II receptor is the main regulator in downstream signal transduction, it is possible to control activin signal transduction by controlling action of the type II receptor.ActR IIA is one of the type II receptor. In the previous studies, the high expression of ActR IIA was observed by imrnunocytochemistry in mouse macrophages. The antibody of anti-ActR IIA blocked the binding of ActR IIA with activin, inhibited the secretion of inflammatory factor of mouse macrophage, such as NO. This showed that ActR IIA is the major receptor which mediates activin effect on macrophages.In order to elucidate the role of ActR IIA in signal transduction of activin in macrophages, the timetable of ActR IIA mRNA expression in mouse macrophages stimulated by activin A was observed. The results revealed that the expression level of ActR IIA mRNA increase gradually, and reached to a high level at 8 hour, and then decreased gradually. The time curve of ActR IIA mRNA expression shows a kind of regulation mechanism to keep physiologic balance.As activin participates the inflammatory reaction, the expression of the ActR IIA mRNA in macrophage stimulated by LPS was further observed. The results of RT-PCR and Western blot showed that LPS inhibited the
expression of ActR II A mRNA in macrophages, and activin A of physiological concentration enhances the ActR IIA mRNA expression in macrophages stimulated by LPS. These findings suggest that LPS reverse the action of activin A in macrophage through repress the expression of ActR II A in the inflammatory reaction.As the inducer of action of mouse macrophages, it seems that there is a kind of mechanism of competition between activin A and LPS. Compared with LPS, activin A is the weak inducer of macrophage, and induces low level of inflammation. In the time of stimulation by strong inducer, LPS, activin competes with the same or related signal transduction pathway with LPS, and shows the action in suppressing the stimulation by LPS. The inter-antagonism between the two of them showed the regulation function in inflammation by activin, and this will be helpful for keeping physiological stabilization and preventing damage from over-response in organism.4-. The effect of ActRIP3 in activin signal transductionActivin receptor-interacting protein 3(ActRIP3) is a novel downstream signal protein in activin signal transduction, which can bind to ActR IIA through the NH2-terminal region, and the COOH-terminal constitute a homology dimer of ActRIP3, but COOH-terminus can't interact with RalBPl, which mediates endocytosis through the NOOH-terminal region. So it doesn't support the opportunity that ActRIP3 acts as a protein in negative feedback regulation of activin signal.In order to investigate the effect mechanism of ActRIP3 in activin signal transduction pathway, pcDNA3-ActRIP3 plasmid was transfected into mouse macrophages of C57/BL, and the production of inflammatory factor
in mouse macrophages was observed by over-expression of ActRIP3. The results showed that the secretion level of NO and the expression of iNOS and IL-1 3 was increased by over expression of ActRIP3. This suggests that ActRIP3 is an important up-regulation signal protein in activin signal pathways.In order to elucidate the effect mechanism of ActRIP3 in activin signal pathway further, the expression of ActRIP3 mRNA in mouse macrophages in different time was observed. The results revealed that the expression of ActRIP3 mRNA reached to a high level at 8 hour, it happened in-synchronism with the expression of ActR IIA mRNA. It suggests that ActRIP3 is up-regulated in activin signal pathway as the similar action of ActR II A.As activin inhibit the activity of macrophage stimulated by LPS, The studies shown that the expression of ActRIP3 mRNA in mouse macrophages stimulated by LPS. The results shown that the expression of ActRIP3 mRNA was decreased in cells stimulated by LPS, but the expression level of ActRIP3 mRNA in cells stimulated by LPS can be increased partially by activin A. The results indicate that there is a kind of competition or cross mechanism between LPS and activin A in signal transduction pathway.5^ The action of ActRIP2 in activin signal transductionActivin receptor-interacting protein 2(ActRIP2) which observed in the previous research is a regulatory molecules in Activin-ActR IIA signal transduction pathway. ARIP2 binds to ActR IIA through the NH2-terminal region, the COOH-terminal constitute a homology dimer of ActRIP2 with hydrophobic bond that interacts with RalBPl(Ral-bingding protein 1) and mediates endocytosis. ActRIP2 decreases the expression of activin receptor
through the induced endocytosis, and inhibits signal transduction of activin.In order to elucidate the effect mechanism of ActRIP2 in activin signal pathway on macrophage, pcDNA3-ActRIP2 vector was transfected into mouse macrophages of C57 BL/6, and the production of inflammatory factor in the cells was observed by over expression of ActRIP2. The results showed that the secretion level of NO and the expression level of iNOS and IL-1 P was decreased by over expression of ActRIP2. This suggests that ActRIP2 participated in regulation of negative feedback in activin signal pathways in mouse macrophage.In order to reveal the mechanism of signal transduction pathway, the expression timetable of ActRIP2 in mouse macrophages stimulated by activin was observed further. The results showed that the expression of ActRIP2 mRNA increased gradually in 8 hour later, and reach to a high level at 24 hour. The time of high level on ActRIP2 mRNA expression is later than ActR IIA and ActRIP3 mRNA (8hour reach to the high level) , indicate that ActRIP2 participate the negative feedback regulation in the later period of activin signal transduction.As a multifunctional factor, Activin has extensive tissue expression, and its receptor is widely expressed in tissue and cells. The study of signal mechanism will reveal the important action of activin in inflammatory reaction, and provide new research evidence in related disease treatment.
巨噬细胞不仅具有分泌细胞因子、NO等作用,还是重要的吞噬细胞。因此,本研究采用原代培养C57BL/6小鼠腹腔巨噬细胞、传代培养BALB/c小鼠巨噬细胞系RAW264.7细胞为实验对象,通过分析IL-1β、NO的分泌、IL-1β、iNOS mRNA表达及细胞吞噬活性,系统探讨激活素A对巨噬细胞活性的双向调控作用。实验表明,激活素A刺激小鼠巨噬细胞炎性因子产生、增强吞噬活性,具有剂量依赖关系;而对LPS活化小鼠巨噬细胞的活性具有明显抑制作用。提示激活素对巨噬细胞的分泌活性和吞噬活性,均具有双向调节作用,此作用与巨噬细胞的激活状态有关。其作用有助于维持机体生理平衡,防止因炎症反应过度而造成的损害。
激活素对细胞的作用具有明显的组织学特异性,其作用的特异性与其受体后信号传导差异有关,前期研究表明巨噬细胞高表达激活素Ⅱ型受体(ActRⅡA)。围绕ActRⅡA信号传导途径的研究,发现了新的信号调控蛋白——激活素受体相互作用蛋白(ActRIP),为明确ActRIPs参与巨噬细胞活性调控的信号传导机制。实验采用基因过表达技术,将ActRIP2、3导入小鼠巨噬细胞,结果显示,ActRIP2抑制小鼠巨噬细胞NO的分泌及iNOS、IL-1 mRNA表达,而ActRIP3促进NO的分泌及iNOS、IL-1 mRNA表达。激活素刺激小鼠巨噬细胞
Activin is synthesized in multiple tissues, and effect on multiple tissues as autocrine and paracrine factors. Abnormal expression of activin was found in patients of inflammatory disease such as hepatic fibrosis, pulmonary fibrosis, arthritis and meningitis etc. Recently more and more evidence indicated that activin relates with inflammation and acute phase reaction closely.1、Activin A enhance the activities of mouse macrophagesMacrophages are the main cells that participate in inflammatory reaction. It is not only the cell secreting cytokines and NO, but also the significant phagocytes. In order to clarified the effect of activin on macrophages which participate inflammatory reaction, firstly, we observed the activity of primary-cultured peritoneal macrophage stimulated by Activin A in C57/BL mouse and that in RAW264.7 cells line of BALB/c mouse.The results showed that activin enhanced the secretion of IL-1β and NO and expression of IL-1β mRNA and iNOS mRNA in primary-cultured macrophages of mouse in a dose-dependent manner. Activin also enhanced the secretion of IL-1β and NO and expression of IL-1β mRNA and iNOS mRNA in RAW264.7 cells line of BALB/c mouse. These data suggest that activin stimulates the production and secretion of IL-1β and NO in the transcription level.
In addition, activin A enhanced the phagocytosis in the wild mouse macrophages and RAW264.7 cells. These results suggest that activin A enhances the activities of mouse macrophage such as the secretion of inflammatory factor and phagocytosis in macrophages.2-. Activin A regulating the inflammation reaction by suppressing the activities of mouse macrophages stimulated by LPSMacrophages are not only the important antigen presentation cells, but also the effective cells in inflammation. In order to clarify the mechanism of activin in inflammation, the effect of activin A on activity of LPS-activated macrophage was observed in this study. The results showed that LPS increase the secretion of IL-1 P and NO, and the expression of IL-1 P and iNOS mRNA, and enhanced phagocytosis of mouse macrophages. Activin of physiological concentration inhibited the secretion of inflammatory factor and phagocytosis of mouse macrophages stimulated by LPS in a dose-dependent manner. This result suggests that activin suppress the activity of macrophage stimulated by LPS.Activin enhances the activity of mouse peritoneal macrophages, and inhibits the production of inflammatory and phagocytosis of LPS-activated macrophages. It suggests that activin shows the function of two-ways in regulating the activity of macrophage. The manner of regulation is related with the inflammation state. And this is help for keeping physiologic equilibrium of organism, and preventing the damage caused by over-response to inflammation. The elucidation of correlation mechanism will provide some new idea to explore the treatment in disease of inflammation.3% The study of relationship between Activin IIA and macrophage
activationThe receptor of .activin is widely expressed in the cells of gonad gland and other tissue out of gonad gland. It is the necessary receptor molecule in keeping growth and differentiation of cells. In activin signal transduction pathways, activin firstly binds to the type II receptor, and type II receptor lead to phosphorylation of the type I receptor. Then, the type I receptor interacts with intracellular signaling molecules, and transfer the signaling into nucleus. As type II receptor is the main regulator in downstream signal transduction, it is possible to control activin signal transduction by controlling action of the type II receptor.ActR IIA is one of the type II receptor. In the previous studies, the high expression of ActR IIA was observed by imrnunocytochemistry in mouse macrophages. The antibody of anti-ActR IIA blocked the binding of ActR IIA with activin, inhibited the secretion of inflammatory factor of mouse macrophage, such as NO. This showed that ActR IIA is the major receptor which mediates activin effect on macrophages.In order to elucidate the role of ActR IIA in signal transduction of activin in macrophages, the timetable of ActR IIA mRNA expression in mouse macrophages stimulated by activin A was observed. The results revealed that the expression level of ActR IIA mRNA increase gradually, and reached to a high level at 8 hour, and then decreased gradually. The time curve of ActR IIA mRNA expression shows a kind of regulation mechanism to keep physiologic balance.As activin participates the inflammatory reaction, the expression of the ActR IIA mRNA in macrophage stimulated by LPS was further observed. The results of RT-PCR and Western blot showed that LPS inhibited the
expression of ActR II A mRNA in macrophages, and activin A of physiological concentration enhances the ActR IIA mRNA expression in macrophages stimulated by LPS. These findings suggest that LPS reverse the action of activin A in macrophage through repress the expression of ActR II A in the inflammatory reaction.As the inducer of action of mouse macrophages, it seems that there is a kind of mechanism of competition between activin A and LPS. Compared with LPS, activin A is the weak inducer of macrophage, and induces low level of inflammation. In the time of stimulation by strong inducer, LPS, activin competes with the same or related signal transduction pathway with LPS, and shows the action in suppressing the stimulation by LPS. The inter-antagonism between the two of them showed the regulation function in inflammation by activin, and this will be helpful for keeping physiological stabilization and preventing damage from over-response in organism.4-. The effect of ActRIP3 in activin signal transductionActivin receptor-interacting protein 3(ActRIP3) is a novel downstream signal protein in activin signal transduction, which can bind to ActR IIA through the NH2-terminal region, and the COOH-terminal constitute a homology dimer of ActRIP3, but COOH-terminus can't interact with RalBPl, which mediates endocytosis through the NOOH-terminal region. So it doesn't support the opportunity that ActRIP3 acts as a protein in negative feedback regulation of activin signal.In order to investigate the effect mechanism of ActRIP3 in activin signal transduction pathway, pcDNA3-ActRIP3 plasmid was transfected into mouse macrophages of C57/BL, and the production of inflammatory factor
in mouse macrophages was observed by over-expression of ActRIP3. The results showed that the secretion level of NO and the expression of iNOS and IL-1 3 was increased by over expression of ActRIP3. This suggests that ActRIP3 is an important up-regulation signal protein in activin signal pathways.In order to elucidate the effect mechanism of ActRIP3 in activin signal pathway further, the expression of ActRIP3 mRNA in mouse macrophages in different time was observed. The results revealed that the expression of ActRIP3 mRNA reached to a high level at 8 hour, it happened in-synchronism with the expression of ActR IIA mRNA. It suggests that ActRIP3 is up-regulated in activin signal pathway as the similar action of ActR II A.As activin inhibit the activity of macrophage stimulated by LPS, The studies shown that the expression of ActRIP3 mRNA in mouse macrophages stimulated by LPS. The results shown that the expression of ActRIP3 mRNA was decreased in cells stimulated by LPS, but the expression level of ActRIP3 mRNA in cells stimulated by LPS can be increased partially by activin A. The results indicate that there is a kind of competition or cross mechanism between LPS and activin A in signal transduction pathway.5^ The action of ActRIP2 in activin signal transductionActivin receptor-interacting protein 2(ActRIP2) which observed in the previous research is a regulatory molecules in Activin-ActR IIA signal transduction pathway. ARIP2 binds to ActR IIA through the NH2-terminal region, the COOH-terminal constitute a homology dimer of ActRIP2 with hydrophobic bond that interacts with RalBPl(Ral-bingding protein 1) and mediates endocytosis. ActRIP2 decreases the expression of activin receptor
through the induced endocytosis, and inhibits signal transduction of activin.In order to elucidate the effect mechanism of ActRIP2 in activin signal pathway on macrophage, pcDNA3-ActRIP2 vector was transfected into mouse macrophages of C57 BL/6, and the production of inflammatory factor in the cells was observed by over expression of ActRIP2. The results showed that the secretion level of NO and the expression level of iNOS and IL-1 P was decreased by over expression of ActRIP2. This suggests that ActRIP2 participated in regulation of negative feedback in activin signal pathways in mouse macrophage.In order to reveal the mechanism of signal transduction pathway, the expression timetable of ActRIP2 in mouse macrophages stimulated by activin was observed further. The results showed that the expression of ActRIP2 mRNA increased gradually in 8 hour later, and reach to a high level at 24 hour. The time of high level on ActRIP2 mRNA expression is later than ActR IIA and ActRIP3 mRNA (8hour reach to the high level) , indicate that ActRIP2 participate the negative feedback regulation in the later period of activin signal transduction.As a multifunctional factor, Activin has extensive tissue expression, and its receptor is widely expressed in tissue and cells. The study of signal mechanism will reveal the important action of activin in inflammatory reaction, and provide new research evidence in related disease treatment.
引文
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