Pim-1信号在小鼠溃疡性结肠炎发病机制中的免疫调节作用研究
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摘要
研究背景
炎症性肠病(IBD)是一组反复发作非特异性的肠道炎症性疾病,发病机制至今尚未完全阐明,但免疫因素在IBD中重要作用已被广大学者所公认。Pim-1基因最初是在鼠白血病病毒(MuLV)诱导的T-细胞淋巴瘤中发现的,目前研究表明Pim-1激酶在细胞增殖、分化、凋亡、肿瘤发生等许多生理病理过程中起重要作用,近年来Pim-1在免疫系统的作用逐渐受到重视,参与控制T淋巴细胞的增殖与凋亡,但是目前关于Pim-1信号是否能调节IBD肠粘膜固有及适应性免疫细胞功能的研究国内外尚未见报道。本课题利用DSS诱导急性小鼠溃疡性结肠炎模型,以观察Pim-1表达与肠道炎症程度关系为切入点,进一步使用Pim-1抑制剂,观察对小鼠溃疡性结肠炎的治疗作用,并探讨对Th1/Th2、Treg/Th17细胞分化的影响,同时探讨Pim-1信号在巨噬细胞激活方面的作用,本课题从动物、细胞、分子水平多方面来探讨Pim-1信号通路对小鼠溃疡性结肠炎肠粘膜固有及适应性免疫细胞功能的调节作用,以阐明Pim-1信号与肠道异常免疫反应的关系,为溃疡性结肠炎的治疗提供新的靶点、为深入Pim-1信号的药理研发提供理论基础。
第一章Pim-1在小鼠急性溃疡性结肠炎模型中的表达
目的：观察Pim-1在溃疡性结肠炎发病过程中的动态表达,并观察其与炎症程度的相关性。方法：BALB/c小鼠饮用5%DSS溶液建立急性溃疡性结肠炎模型,分别在第0、1、4、7天取结肠标本,利用real time PCR、Western Blot及免疫组化动态观察Pim-1表达,分析Pim-1的表达和DAI、组织学炎症评分的相关性。结果：①饮用5%DSS7天后成功建立小鼠急性溃疡性结肠炎动物模型,②real time PCR、Western Blot结果显示在饮用5%DSS第4、7天后Pim-1表达较正常组及第1天均明显升高,P<0.05,免疫组化显示Pim-1主要在淋巴细胞、中性粒细胞等炎症细胞表达。③Pearman相关分析表明,结肠组织中Pim-1蛋白与DAI呈正相关(R=0.868,P<0.01),与组织病理学评分亦呈正相关(R=0.851,P<0.01)。结论：在溃疡性结肠炎起病过程中Pim-1的表达与肠道炎症程度呈正相关,Pim-1信号参与肠道炎症反应。
第二章Pim-1信号对Th细胞分化、及巨噬细胞激活的影响
目的：用PIM-Inh阻断Pim-1信号,观察对DSS诱导的小鼠溃疡性结肠炎的治疗作用,同时研究PIM-Inh对肠粘膜中Th细胞分化及巨噬细胞激活的影响。方法：①应用PIM-Inh阻断Pim-1信号,治疗7天后,观察对DSS诱导小鼠溃疡性结肠炎的治疗作用,②ELISA检测Th细胞因子(IL4, TGF-β, IFN-γ, IL17),③real time PCR、 Western Blot检测Th细胞转录因子的表达(GATA3, T-bet, Foxp3, RORrt),④Western Blot检测肠道组织巨噬细胞激活标记物NF-κB,iNOS的表达。结果：①PIM-Inh治疗组小鼠血便、腹泻症状、DAI评分、病理组织学评分较DSS模型组均好转,②与DSS模型组比较,PIM-Inh治疗组肠组织中IFNγ、IL17表达下降,P<0.05,差别具有统计学意义,其中高剂量治疗组下降更加明显；PIM-Inh治疗组肠组织中TGFβ的表达较模型组升高,其高剂量组升高较明显,P<0.05,而低剂量治疗组与模型组比较,P>0.05,差别无统计学意义；PIM-Inh治疗组肠组织中IL4的表达较DSS模型组稍下降,但P>0.05,差别无统计学意义,③real time PCR. Western Blot结果显示：PIM-Inh治疗组肠组织中T-bet, ROR-γt较DSS模型组明显下降,而FOXP3的表达比模型组明显升高,P<0.05,差别无统计学意义,但是对GATA-3的表达无明显影响,④PIM-Inh治疗组肠组织中p-NF-κB P65, iNOS的表达较DSS模型组明显下降,P<0.05。结论：阻断Pim-1信号可抑制巨噬细胞活化、抑制Thl、Thl7为主的炎症反应,促进向Treg细胞分化,从而对DSS诱导的小鼠溃疡性结肠炎具有治疗作用。
第三章Pim-1对TLR4/NF-KB信号通路的调节
目的：观察LPS对Pim-1表达的影响,阻断Pim-1对TLR4/NF-KB信号通路的影响方法：①不同剂量LPS作用于RAW264.7巨噬细胞,分别在12h、24h后用real timePCR及Western Blot检测Pim-1的表达,②在LPS刺激前给予Pim-1特异性抑制齐(PIM-Inh), Western Blot检测pNF-kB P65的表达,ELISA测定TNF-α的表达。结果：①与正常对照比较,100ng/ml,1ug/ml的LPS均可以促进Pim-1的表达,其中1ug/ml更加明显,P<0.05,差别具有统计学意义；同一浓度LPS作用12h后比24h后Pim-1升高更加明显,P<0.05,差别具有统计学意义②用10umol/L,100umol/L PIM-Inh预处理后,NF-κBp65、TNFa蛋白的表达下降,且呈剂量依赖性,即浓度100umol/L时最为明显,P<0.05,差别具有统计学意义；而1umol/L PIM-Inh预处理后对NF-κBp65蛋白表达无明显影响,P>0.05,差别无统计学意义。结论：LPS可以诱导Pim-1的表达,阻断Pim-1可以抑制TLR4/NF-κB信号转导。
Background
Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract. Although the etiology of IBD remains unclear, accumulating evidence has indicated that dysfunction of the mucosal immune system plays an important role in the pathogenesis of IBD, Pim-1is a serine/threonine kinase that was first discovered as a preferential proviral insertion site in Moloney Murine Leukemia Virus (MoMuLV) induced T-cell lymphomas, Pim-1kinase is involved in the control of cell growth, differentiation and apoptosis. Accumulating data support that Pim-1are essential components of an endogenous pathway that regulates T cell growth and survival. The crucial role of Pim kinase in immune cells activation and proliferation makes it an attractive target for immunomodulatory therapy. Indeed, the pharmacological inhibition of Pim kinases exhibits immunomodulatory benefits, However, it remains unclear whether pim-1kinase is involved in the pathology of ulcerative colitis and whether pim-1kinase could modulate T help cell differentiation and macrophage activation during the development of ulcerative colitis.
The aims of this study were to explore the role of Pim-1kinase in the pathology of ulcerative colitis and to assess whether Pim-1kinase may act to regulate innate and adaptive immune responses,inhibiting Pim-1kinase may be of therapeutic benefit as a treatment regimen for ulcerative colitis. In vitro effects of Pim-1on LPS-induced macrophage activation as well as in vivo effects of PIM-Inhibitor (PIM-Inh) in mice with DSS-induced colitis, were explored.Colon inflammation, production of proinflammatory cytokines and NF-κB activation in colon tissues,and The expression of T cell master transcription factors were were assayed.In summary, our data may provide evidence that Pim-1may act as a central regulator in the immune response by regulates macrophages activation and Th cells differentiation.These findings may offer a promising alternative to our current approaches of managing ulcerative colitis.
The first chapter:Expression of Pim-1kinases in Mice Colitis Model that Acute Colitis Induced with DSS
Objective:To explore the role of Pim-1in the initiation and development of ulcerative colitis Methods:We examined Pim-1mRNA and protein expression in colonic samples by real-time quantitative reverse transcription-PCR, Western blot and Immunohistochemical Staining Methods, at0,1,4and7days after mice were induced by giving5%DSS, The correlation between the two parameters was tested using the Pearson correlation test,P<0.05was considered to be statistically significant. Result:①The animals treated with5%DSS for7days developed symptoms of acute colitis at an incidence of100%, exhibited body weight loss and showed watery or bloody diarrhea beginning on day4of the DSS administration,②Increased amounts of Pim-1were observed as soon as1day after starting DSS,the difference was not, however, significant,The Pim-1protein expression were significantly higher on day7than on day4,or on day1, Consistent with the Western blot result,Relatively high concentrations of Pim-1mRNA occurred in colon tissue at4days of DSS treatment,reaching their highest point at day7,③Pearson correlation analysis revealed a strong positive correlation between DAI and expression of Pim-1(R=0.868,P<0.01), between histological disease scores and expression of Pim-1(R=0.851, P<0.01) Conclusion:We observed that the expression of pim-1correlated with the degree of mucosal inflammation in vivo,These data suggest that pim-1kinase may be involved in the development of ulcerative colitis.
The second chapter:Research on mechanisms of Pim-1kinase in modulation of T-cell differentiation and Macrophage Activation in DSS-Induced Acute Colitis.
Objective:The aim of this study was to understand more about the role of Pim-1kinase in contributing to the pathology of ulcerative colitis and to assess whether blocking Pim-1kinase may be of therapeutic benefit as a treatment regimen for ulcerative colitis. Methods:Mice with acute colitis induced by5%DSS were treated with or without PIM-Inh,Body weight and colon inflammation were evaluated,and production of lymphocytes cytokines (IFN-γ,IL-4, TGF-β,IL-17) in colon tissues was determined by ELSIA.The expression of T cell master transcription factors(T-bet, ROR-yt,GATA-3,Foxp3)were measured by Real-Time qRT-PCR and Western Blot. Nuclear factorκB (NF-κB) and inducible nitric oxide synthase(iNOS) activation in colon tissues was assayed. Result:①the PIM-Inh had protective and therapeutic potentials in acute DSS colitis in vivo②treatment with PIM-Inh inhibited the production of IFN-y and IL-17in a dose-dependent manner,The production of TGF-β was higher in PIM-Inh (10mg/kg/d)treated mice as compared to either DSS or PIM-Inh (5mg/kg/d) treated mice(P<0.05), Production of IL-4in PIM-Inh treated mice was intermediate between that of control group and DSS treated mice, the difference was not, however, significant③In this study,T-bet,ROR-yt was significantly up-regulated in acute ongoing DSS colitis,In contrast,The expression of Foxp3was inhibited in DSS group mice,Administration of PIM-Inh resulted in inhibition of T-bet,ROR-yt expression in a dose-dependent manner and the induction of FOXP3expression,whereas PIM-Inh did not cause any significant change in GATA-3expression compared with DSS colitis group,④in Acute Colitis mice, pNF-κB and iNOS expression in colon tissues are significantly increased. PIM-Inh treatment significantly inhibited NF-κB activation and thus down-regulated iNOS expression in colon tissues of mice in a dose-dependent manner,compared with mice without PIM-Inh treatment.Conclusion:we found that PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Thl-and Th17-type immune responses, Furthermore, PIM-Inh could skew T-cell differentiation towards a Treg phenotype.These results indicate that Pim-1kinase is involved in the pathophysiology of ulcerative colitis.
The third chapter:Effects of Pim-1on TLR4/NF-kBsignaling in vitro
Objective:To investigate pim-1activation induced by LPS in macrophages and to explore whether PIM-Inh inhibits LPS-induced macrophage activation in vitro.Methods:①we identified the expressions of Pim-1in RAW264.7cells incubated with different doses of LPS by Western blotting and real-time PCR, respectively at different time points (12,24h),②RAW264.7were pretreated with different doses of PIM-Inh2h before addition of LPS (1ug/mL). The expression of pNF-kB P65was detected by Western blot1.5h after LPS activation. The levels of TNFa in the supernatants, collected24h after LPS stimulation, were assayed by ELISA.Result:①treatment of RAW264.7with LPS increases expressions of mRNA Pim-1in a dose-dependent manner, expressions of Pim-1was significantly increased at12hours after incubation with LPS,which was slightly higher at12hours than that detected at24hours,p<0.05,Significantly different from normol group②When the macrophages were treated with PIM-Inh,the expression of phosphorylated-NF-kB P65and TNFa production were inhibited in a dose-dependent pattern, Treatment with100umol/L PIM-Inh achieves the highest inhibitory effect on TNFa production,p<0.05,Significantly different from the group with LPS treatment. Conclusion:data suggest that treatment with LPS increases Pim-1production in a dose-dependent manner,PIM-Inh administration inhibited NF-κB activation,which subsequently resulted in a down-regulation of iNOS expression in macrophages and an inhibition of TNF production.
炎症性肠病(IBD)是一组反复发作非特异性的肠道炎症性疾病,发病机制至今尚未完全阐明,但免疫因素在IBD中重要作用已被广大学者所公认。Pim-1基因最初是在鼠白血病病毒(MuLV)诱导的T-细胞淋巴瘤中发现的,目前研究表明Pim-1激酶在细胞增殖、分化、凋亡、肿瘤发生等许多生理病理过程中起重要作用,近年来Pim-1在免疫系统的作用逐渐受到重视,参与控制T淋巴细胞的增殖与凋亡,但是目前关于Pim-1信号是否能调节IBD肠粘膜固有及适应性免疫细胞功能的研究国内外尚未见报道。本课题利用DSS诱导急性小鼠溃疡性结肠炎模型,以观察Pim-1表达与肠道炎症程度关系为切入点,进一步使用Pim-1抑制剂,观察对小鼠溃疡性结肠炎的治疗作用,并探讨对Th1/Th2、Treg/Th17细胞分化的影响,同时探讨Pim-1信号在巨噬细胞激活方面的作用,本课题从动物、细胞、分子水平多方面来探讨Pim-1信号通路对小鼠溃疡性结肠炎肠粘膜固有及适应性免疫细胞功能的调节作用,以阐明Pim-1信号与肠道异常免疫反应的关系,为溃疡性结肠炎的治疗提供新的靶点、为深入Pim-1信号的药理研发提供理论基础。
第一章Pim-1在小鼠急性溃疡性结肠炎模型中的表达
目的：观察Pim-1在溃疡性结肠炎发病过程中的动态表达,并观察其与炎症程度的相关性。方法：BALB/c小鼠饮用5%DSS溶液建立急性溃疡性结肠炎模型,分别在第0、1、4、7天取结肠标本,利用real time PCR、Western Blot及免疫组化动态观察Pim-1表达,分析Pim-1的表达和DAI、组织学炎症评分的相关性。结果：①饮用5%DSS7天后成功建立小鼠急性溃疡性结肠炎动物模型,②real time PCR、Western Blot结果显示在饮用5%DSS第4、7天后Pim-1表达较正常组及第1天均明显升高,P<0.05,免疫组化显示Pim-1主要在淋巴细胞、中性粒细胞等炎症细胞表达。③Pearman相关分析表明,结肠组织中Pim-1蛋白与DAI呈正相关(R=0.868,P<0.01),与组织病理学评分亦呈正相关(R=0.851,P<0.01)。结论：在溃疡性结肠炎起病过程中Pim-1的表达与肠道炎症程度呈正相关,Pim-1信号参与肠道炎症反应。
第二章Pim-1信号对Th细胞分化、及巨噬细胞激活的影响
目的：用PIM-Inh阻断Pim-1信号,观察对DSS诱导的小鼠溃疡性结肠炎的治疗作用,同时研究PIM-Inh对肠粘膜中Th细胞分化及巨噬细胞激活的影响。方法：①应用PIM-Inh阻断Pim-1信号,治疗7天后,观察对DSS诱导小鼠溃疡性结肠炎的治疗作用,②ELISA检测Th细胞因子(IL4, TGF-β, IFN-γ, IL17),③real time PCR、 Western Blot检测Th细胞转录因子的表达(GATA3, T-bet, Foxp3, RORrt),④Western Blot检测肠道组织巨噬细胞激活标记物NF-κB,iNOS的表达。结果：①PIM-Inh治疗组小鼠血便、腹泻症状、DAI评分、病理组织学评分较DSS模型组均好转,②与DSS模型组比较,PIM-Inh治疗组肠组织中IFNγ、IL17表达下降,P<0.05,差别具有统计学意义,其中高剂量治疗组下降更加明显；PIM-Inh治疗组肠组织中TGFβ的表达较模型组升高,其高剂量组升高较明显,P<0.05,而低剂量治疗组与模型组比较,P>0.05,差别无统计学意义；PIM-Inh治疗组肠组织中IL4的表达较DSS模型组稍下降,但P>0.05,差别无统计学意义,③real time PCR. Western Blot结果显示：PIM-Inh治疗组肠组织中T-bet, ROR-γt较DSS模型组明显下降,而FOXP3的表达比模型组明显升高,P<0.05,差别无统计学意义,但是对GATA-3的表达无明显影响,④PIM-Inh治疗组肠组织中p-NF-κB P65, iNOS的表达较DSS模型组明显下降,P<0.05。结论：阻断Pim-1信号可抑制巨噬细胞活化、抑制Thl、Thl7为主的炎症反应,促进向Treg细胞分化,从而对DSS诱导的小鼠溃疡性结肠炎具有治疗作用。
第三章Pim-1对TLR4/NF-KB信号通路的调节
目的：观察LPS对Pim-1表达的影响,阻断Pim-1对TLR4/NF-KB信号通路的影响方法：①不同剂量LPS作用于RAW264.7巨噬细胞,分别在12h、24h后用real timePCR及Western Blot检测Pim-1的表达,②在LPS刺激前给予Pim-1特异性抑制齐(PIM-Inh), Western Blot检测pNF-kB P65的表达,ELISA测定TNF-α的表达。结果：①与正常对照比较,100ng/ml,1ug/ml的LPS均可以促进Pim-1的表达,其中1ug/ml更加明显,P<0.05,差别具有统计学意义；同一浓度LPS作用12h后比24h后Pim-1升高更加明显,P<0.05,差别具有统计学意义②用10umol/L,100umol/L PIM-Inh预处理后,NF-κBp65、TNFa蛋白的表达下降,且呈剂量依赖性,即浓度100umol/L时最为明显,P<0.05,差别具有统计学意义；而1umol/L PIM-Inh预处理后对NF-κBp65蛋白表达无明显影响,P>0.05,差别无统计学意义。结论：LPS可以诱导Pim-1的表达,阻断Pim-1可以抑制TLR4/NF-κB信号转导。
Background
Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract. Although the etiology of IBD remains unclear, accumulating evidence has indicated that dysfunction of the mucosal immune system plays an important role in the pathogenesis of IBD, Pim-1is a serine/threonine kinase that was first discovered as a preferential proviral insertion site in Moloney Murine Leukemia Virus (MoMuLV) induced T-cell lymphomas, Pim-1kinase is involved in the control of cell growth, differentiation and apoptosis. Accumulating data support that Pim-1are essential components of an endogenous pathway that regulates T cell growth and survival. The crucial role of Pim kinase in immune cells activation and proliferation makes it an attractive target for immunomodulatory therapy. Indeed, the pharmacological inhibition of Pim kinases exhibits immunomodulatory benefits, However, it remains unclear whether pim-1kinase is involved in the pathology of ulcerative colitis and whether pim-1kinase could modulate T help cell differentiation and macrophage activation during the development of ulcerative colitis.
The aims of this study were to explore the role of Pim-1kinase in the pathology of ulcerative colitis and to assess whether Pim-1kinase may act to regulate innate and adaptive immune responses,inhibiting Pim-1kinase may be of therapeutic benefit as a treatment regimen for ulcerative colitis. In vitro effects of Pim-1on LPS-induced macrophage activation as well as in vivo effects of PIM-Inhibitor (PIM-Inh) in mice with DSS-induced colitis, were explored.Colon inflammation, production of proinflammatory cytokines and NF-κB activation in colon tissues,and The expression of T cell master transcription factors were were assayed.In summary, our data may provide evidence that Pim-1may act as a central regulator in the immune response by regulates macrophages activation and Th cells differentiation.These findings may offer a promising alternative to our current approaches of managing ulcerative colitis.
The first chapter:Expression of Pim-1kinases in Mice Colitis Model that Acute Colitis Induced with DSS
Objective:To explore the role of Pim-1in the initiation and development of ulcerative colitis Methods:We examined Pim-1mRNA and protein expression in colonic samples by real-time quantitative reverse transcription-PCR, Western blot and Immunohistochemical Staining Methods, at0,1,4and7days after mice were induced by giving5%DSS, The correlation between the two parameters was tested using the Pearson correlation test,P<0.05was considered to be statistically significant. Result:①The animals treated with5%DSS for7days developed symptoms of acute colitis at an incidence of100%, exhibited body weight loss and showed watery or bloody diarrhea beginning on day4of the DSS administration,②Increased amounts of Pim-1were observed as soon as1day after starting DSS,the difference was not, however, significant,The Pim-1protein expression were significantly higher on day7than on day4,or on day1, Consistent with the Western blot result,Relatively high concentrations of Pim-1mRNA occurred in colon tissue at4days of DSS treatment,reaching their highest point at day7,③Pearson correlation analysis revealed a strong positive correlation between DAI and expression of Pim-1(R=0.868,P<0.01), between histological disease scores and expression of Pim-1(R=0.851, P<0.01) Conclusion:We observed that the expression of pim-1correlated with the degree of mucosal inflammation in vivo,These data suggest that pim-1kinase may be involved in the development of ulcerative colitis.
The second chapter:Research on mechanisms of Pim-1kinase in modulation of T-cell differentiation and Macrophage Activation in DSS-Induced Acute Colitis.
Objective:The aim of this study was to understand more about the role of Pim-1kinase in contributing to the pathology of ulcerative colitis and to assess whether blocking Pim-1kinase may be of therapeutic benefit as a treatment regimen for ulcerative colitis. Methods:Mice with acute colitis induced by5%DSS were treated with or without PIM-Inh,Body weight and colon inflammation were evaluated,and production of lymphocytes cytokines (IFN-γ,IL-4, TGF-β,IL-17) in colon tissues was determined by ELSIA.The expression of T cell master transcription factors(T-bet, ROR-yt,GATA-3,Foxp3)were measured by Real-Time qRT-PCR and Western Blot. Nuclear factorκB (NF-κB) and inducible nitric oxide synthase(iNOS) activation in colon tissues was assayed. Result:①the PIM-Inh had protective and therapeutic potentials in acute DSS colitis in vivo②treatment with PIM-Inh inhibited the production of IFN-y and IL-17in a dose-dependent manner,The production of TGF-β was higher in PIM-Inh (10mg/kg/d)treated mice as compared to either DSS or PIM-Inh (5mg/kg/d) treated mice(P<0.05), Production of IL-4in PIM-Inh treated mice was intermediate between that of control group and DSS treated mice, the difference was not, however, significant③In this study,T-bet,ROR-yt was significantly up-regulated in acute ongoing DSS colitis,In contrast,The expression of Foxp3was inhibited in DSS group mice,Administration of PIM-Inh resulted in inhibition of T-bet,ROR-yt expression in a dose-dependent manner and the induction of FOXP3expression,whereas PIM-Inh did not cause any significant change in GATA-3expression compared with DSS colitis group,④in Acute Colitis mice, pNF-κB and iNOS expression in colon tissues are significantly increased. PIM-Inh treatment significantly inhibited NF-κB activation and thus down-regulated iNOS expression in colon tissues of mice in a dose-dependent manner,compared with mice without PIM-Inh treatment.Conclusion:we found that PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Thl-and Th17-type immune responses, Furthermore, PIM-Inh could skew T-cell differentiation towards a Treg phenotype.These results indicate that Pim-1kinase is involved in the pathophysiology of ulcerative colitis.
The third chapter:Effects of Pim-1on TLR4/NF-kBsignaling in vitro
Objective:To investigate pim-1activation induced by LPS in macrophages and to explore whether PIM-Inh inhibits LPS-induced macrophage activation in vitro.Methods:①we identified the expressions of Pim-1in RAW264.7cells incubated with different doses of LPS by Western blotting and real-time PCR, respectively at different time points (12,24h),②RAW264.7were pretreated with different doses of PIM-Inh2h before addition of LPS (1ug/mL). The expression of pNF-kB P65was detected by Western blot1.5h after LPS activation. The levels of TNFa in the supernatants, collected24h after LPS stimulation, were assayed by ELISA.Result:①treatment of RAW264.7with LPS increases expressions of mRNA Pim-1in a dose-dependent manner, expressions of Pim-1was significantly increased at12hours after incubation with LPS,which was slightly higher at12hours than that detected at24hours,p<0.05,Significantly different from normol group②When the macrophages were treated with PIM-Inh,the expression of phosphorylated-NF-kB P65and TNFa production were inhibited in a dose-dependent pattern, Treatment with100umol/L PIM-Inh achieves the highest inhibitory effect on TNFa production,p<0.05,Significantly different from the group with LPS treatment. Conclusion:data suggest that treatment with LPS increases Pim-1production in a dose-dependent manner,PIM-Inh administration inhibited NF-κB activation,which subsequently resulted in a down-regulation of iNOS expression in macrophages and an inhibition of TNF production.
引文
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