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1.
p38 MAPK参与LPS诱导RAW细胞TNF—α基因表达的调控   总被引:3,自引:0,他引:3  
构建TNF-α启动子驱动的荧光酶报告基因系统,研究p38MAPK信号转导系统对TNF-α基因表达的影响,RAW264.7细胞共转染实验发现,LPS对p38的激活作用与其诱导TNF-α转录活性的作用显著相关,虽然单纯转染p38未见明显诱导TNF-α报告基因系统的转录活性。  相似文献   

2.
巨噬细胞免疫调变信号——PKA与PKC对MAPK信号通路的调节   总被引:7,自引:0,他引:7  
以前的研究工作表明,细菌脂多糖(LPS)可以调变抑制性巨噬细胞为增强T、B淋巴细胞及NK细胞活性,同时又能保持或增强其抗肿瘤效应。忆报道了在这一复杂的免疫调变过程中伴随有蛋白激酶C(PKC)和促分裂原活化蛋白激酶(MAPK)信号转导通路的激活。为了探索免疫调变过程中其他信号对MAPK通路的影响,以LPS调变小鼠腹腔抑制性巨噬细胞为模型,研究了cAMP/PKA和佛波酯(PMA)/PKC信号对MAPK  相似文献   

3.
MAPK信号转导通路对炎证反应的调控   总被引:26,自引:2,他引:24  
Jiang Y  Gong XW 《生理学报》2000,52(4):267-271
丝裂原活化蛋白激酶(mitohen-actevatcd protein kinasa,MAPK)是生物体内重要的信号转导系统之一,参与介导生长、发育、化裂、分化、死亡以及细胞间的功能同步等多种细胞过程,在哺乳动物细胞中已发现和克隆了ERK、JNK/SAPK、p38/RK、ERK5/BMK1四个MAPK亚族。这些MAPK能被多种炎性刺激所激活,并对炎症的发生、发展起生重要调控作用。研究感染和炎症反应  相似文献   

4.
通过RNA印迹分析和亚硝酸盐含量测定检查TNF-α、IL-1β和LPS对大鼠血管平滑肌细胞(VSMC)诱导型一氧化氮合酶(iNOS)基因表达及NO生成的影响.结果表明,TNF-α、IL-1β和LPS均能显著诱导VSMCiNOS基因表达和促进NO生成,其作用强度与浓度和作用时间有关;双因素(TNF-α+LPS,LPS+IL-1β)对诱导iNOS基因表达及NO生成产生协同作用.PolymyxinB和地塞米松可部分抑制TNF-α对iNOS基因表达的诱导作用及NO生成  相似文献   

5.
JNK/SAPK信号传递途径与细胞应激反应   总被引:2,自引:0,他引:2  
c-JunNH2-末端激酶(JNK)又称为应激活化蛋白激酶(SAPK),是有丝分裂原活化蛋白激酶(MAPK)家族成员之一。大量研究证实,JNK/SAPK信号传递途径在细胞应激反应中起重要作用。JNK/SAPK信号传递途径的激活促进细胞凋亡发生,其机制与诱导FasL表达、调控凋亡相关基因差异表达和改变细胞内Ca^2+环境与激活caspases家族在关。在某些情况下,JNK/SAPK信号传递途径的激活  相似文献   

6.
通过RNA印迹分析和亚硝酸盐含量测定检查TNF-α、IL-1β和LPS对大鼠血管平滑肌细胞(VSMC)诱导型一氧化氮合酶基因表达及NO生成的影响,结果表明,TNF-α、IL-1β和LPS均能显诱导VSMCiS基因表达和促进NO生成,其作用强度与浓度和作用时间有关;双因素(TNF-α+LPS,LPS+IL-1β)对诱导iNOS基因表达及NO生成产生协同作用,PolymyxinB和地塞米松可部分凶制  相似文献   

7.
溶血磷脂酸的信号转导途径   总被引:6,自引:0,他引:6  
Liu NK  Tang CS 《生理科学进展》1999,30(2):137-140
溶血磷脂酸(LPA)是一种细胞间磷脂信使,它可通过G蛋白偶联受体引起多种生物学效应,如促进血小板聚集,诱导平滑肌收缩,刺激细胞增殖,抑制细胞分化等。最近研究发现G蛋白介导的LPA信号转导途径至少有四种:(1)刺激磷胆酶C和磷脂酶D;(2)抑制腺苷酸环化酶;(3)激活Ras及其下游的Raf/MAPK途径;(4)Rho信号;粘着斑蛋白的酪氨酸磷酸化和肌动蛋白细胞骨架的重组。这些信号转导途径对细胞的增殖  相似文献   

8.
地塞米松(Dex)、噻庚啶(Cyp) 和山莨菪碱(Ani) 对脂多糖(LPS) 诱导的大鼠肝脏TNFα表达的影响。Wistar大鼠40 只, 静脉注射LPS(EcoliO111B4 5m g/kg) 后, 立即静脉给予Dex 5m g/kg、Cyp5m g/kg 或Am i10m g/kg,于LPS攻击后2h 取动物的肝脏,APAAP法进行TNFα免疫组织化学研究,North-ern 杂交分析TNFαm RNA 表达水平。结果发现LPS攻击后2h, 肝脏TNFαm RNA 表达水平显著增高, 肝脏枯否氏细胞胞浆内有大量的TNFα红染颗粒。Dex、Cyp 或Ani均能显著降低大鼠肝脏TNFαm RNA 水平和TNFα含量。结果表明Dex、Cyp 和Ani均显著抑制LPS诱导的TNFα基因表达, 可能有抗感染性休克作用。  相似文献   

9.
细菌内毒素以血管内皮细胞的激活损伤作用   总被引:1,自引:0,他引:1  
细菌内毒素可激活、损伤血管内皮细胞,引起机体产生局部炎症反应和弥散性血管内凝血(DIC)等病理反庆,甚至导致机休我、死亡。内毒素激活血管内皮细胞有两条途径:其一是与LPS结合蛋白、LPS/LPS结合蛋白复合物受体结合后,直接激活血管内皮细胞;其二是先激活单核细胞、T细胞等免疫活性细胞,使其释放TNF-α、IFN和IL-1β等细胞因子,间接激活血管内皮细胞。两条激活途径关系密切,以间接激活途径为主。  相似文献   

10.
巨噬细胞免疫调变信号:Raf—1,MAPKp44,MAPKp42和p38MAPK的研究   总被引:1,自引:0,他引:1  
为了了解巨噬细胞免疫调变机理,我们应用LPS和PMA处理小鼠抑制性巨噬细胞,观察到Ras下游信号分子AF-1,分裂原激活蛋白激酶MAPKp44,MAPKp42和p38MAPK均被活化,发现forskolin能增强p38MAPK的活性,进一步提示PKC和PAK途径增强了p38MAPK的磷酸化效应,为我们了解LPS如何激活p38MAPK信号通路提供了一个新的机会/  相似文献   

11.
LPS (endotoxins) activate cells of the human immune system, among which are monocytes and macrophages, to produce endogenous mediators. These regulate the immune response, but may also cause severe harm leading to septic shock. The activation of monocytes/macrophages by LPS is mediated by a membrane-bound LPS receptor, mCD14. As mCD14 lacks a transmembrane domain, a further protein is required for the signal transducing step to the cell interior. Here we show, using excised outside-out membrane patches, that activation of a high-conductance Ca(2+)- and voltage-dependent potassium channel is an early step in the transmembrane signal transduction in macrophages. The channel is activated by endotoxically active LPS in a dose-dependent manner. Channel activation can be completely inhibited by LPS antagonists and by anti-CD14 Abs. Activation of the channel is essential for LPS-induced cytokine production as shown by its inhibition by selective K(+) channel blockers.  相似文献   

12.
Molecular mechanisms of endotoxin activity   总被引:20,自引:0,他引:20  
Endotoxin (lipopolysaccharide, LPS), a constitutent of the outer membrane of the cell wall of gramnegative bacteria, exerts a wide variety of biological effects in humans. This review focuses on the molecular mechanisms underlying these activities and discusses structure-function relationships of the endotoxin molecule, its interaction with humoral and cellular receptors involved in cell activation, and transmembrane and intra-cellular signal transduction pathways.  相似文献   

13.
We show that both the lipopolysaccharide (LPS)-induced activation of NF-kappa DNA binding and kappa gene expression are blocked by treating murine pre-B lymphocyte 70Z/3 cells with 5'-methylthioadenosine (MTA), an inhibitor of several S-adenosylmethionine-dependent methylation reactions. We further show that the LPS-induced incorporation of radioactivity from [methyl-3H]methionine into methyl ester-like linkages on a group of membrane polypeptides is also inhibited by MTA treatment, suggesting the involvement of protein methylation reactions in the LPS signal transduction pathway. We also find that NF-kappa B and kappa gene activation in LPS-treated 70Z/3 cells is blocked by mevinolin, an inhibitor that prevents protein isoprenylation. Interestingly, mevinolin-treated cells also exhibited a marked reduction in the methylation of membrane proteins. Neither MTA nor mevinolin significantly inhibited NF-kappa B activation by phorbol myristate acetate, suggesting that these agents act early in signal transduction. These results provide the first evidence that carboxyl methylated and/or isoprenylated proteins play an essential role in the LPS-signaling pathway.  相似文献   

14.
15.
Three cell-surface proteins have been recognized as components of the mammalian signaling receptor for bacterial lipopolysaccharide (LPS): CD14, Toll-like receptor-4 (TLR4), and MD-2. Biochemical and visual studies shown here demonstrate that the role of CD14 in signal transduction is to enhance LPS binding to MD-2, although its expression is not essential for cellular activation. These studies clarify how MD-2 functions: we found that MD-2 enables TLR4 binding to LPS and allows the formation of stable receptor complexes. MD-2 must be bound to TLR4 on the cell surface before binding can occur. Consequently, TLR4 clusters into receptosomes (many of which are massive) that recruit intracellular toll/IL-1/resistance domain-containing adapter proteins within minutes, thus initiating signal transduction. TLR4 activation correlates with the ability of MD-2 to bind LPS, as MD-2 mutants that still bind TLR4, but are impaired in the ability to bind LPS, conferred a greatly blunted LPS response. These findings help clarify the earliest events of TLR4 triggering by LPS and identify MD-2 as an attractive target for pharmacological intervention in endotoxin-mediated diseases.  相似文献   

16.
The activation of phagocytes by lipopolysaccharide (LPS) has been implicated in the pathogenesis of Gram-negative sepsis. Although the interaction between CD14 and LPS is a key event in the signaling cascade, the molecular mechanism by which cellular activation occurs remains obscure. We hypothesized that the main function of CD14 was to bind LPS and transfer it to a second receptor, which then initiates the subsequent signal for cellular activation. Thus, surface binding of LPS to the cell membrane would be the critical step that CD14 carries out. To test this hypothesis, we examined the activity of two other proteins known to bind LPS, lipopolysaccharide-binding protein and bactericidal/permeability-increasing protein. We found that when these normally soluble proteins were expressed in Chinese hamster ovary-K1 fibroblasts as glycosylphosphatidylinositol-anchored proteins, both could substitute for CD14 in initiating LPS signaling. Pharmacological studies with synthetic lipid A analogues demonstrated that these surface expressed LPS-binding proteins had characteristics that were qualitatively identical to membrane CD14. These data support the hypothesis that a receptor distinct from CD14 functions as the actual signal transducer and suggest that surface binding of LPS to the cell membrane is the crucial first step for initiating downstream signaling events.  相似文献   

17.
In this study we have identified members of the Toll-like receptor (TLR) family (namely, TLRs 4, 6, 8, and 9) as proteins to which the intracellular protein tyrosine kinase, Bruton's tyrosine kinase (Btk), binds. Detailed analysis of the interaction between Btk and TLR8 demonstrates that the presence of both Box 2 and 3 motifs in the Toll/interleukin-1 receptor domain was required for the interaction. Furthermore, co-immunoprecipitation experiments revealed that Btk can also interact with key proteins involved in TLR4 signal transduction, namely, MyD88, Mal (MyD88 adapter-like protein), and interleukin-1 receptor-associated kinase-1, but not TRAF-6. The ability of Btk to interact with TLR4 and Mal suggests a role for Btk in lipopolysaccharide (LPS) signal transduction. Stimulation of the human monocytic cell line THP-1 with LPS resulted in an increase in the level of tyrosine phosphorylation of Btk (indicative of activation). The autokinase activity of Btk was also stimulated after LPS stimulation. In addition, a dominant negative form of Btk inhibited TLR4-mediated activation of a nuclear factor kappaB (NFkappaB)-dependent reporter gene in HEK293 cells as well as LPS-induced activation of NFkappaB in the astrocytoma cell line U373 and the monocytic cell line RAW264.7. Further investigation revealed that the Btk-specific inhibitor, LFM-A13, inhibited the activation of NFkappaB by LPS in THP-1 cells. Our findings implicate Btk as a Toll/interleukin-1 receptor domain-binding protein that is important for NFkappaB activation by TLR4.  相似文献   

18.
Over the last 20 years the JAK/STAT signal transduction pathway has been extensively studied. An enormous amount of data on different cell signal transduction pathways is now available. The JAK/STAT signal transduction pathway is one of the intracellular signaling pathways activated by cytokines and growth factors that was first studied in the hematopoietic system, but recent data demonstrate that this signal transduction is also greatly utilized by other systems. The JAK/STAT pathway is a signaling cascade that links the activation of specific cell membrane receptors to nuclear gene expression. This review is focused on the role of JAK/STAT signal transduction pathway activation in the central nervous system (CNS).  相似文献   

19.
Gerber IB  Dubery IA 《Phytochemistry》2004,65(22):2957-2966
Bacterial LPS have the ability to act as modulators of the innate immune response in plants. Complex and largely unresolved perception systems exist for LPS on the plant cell surfaces that lead to the activation of multiple intracellular defense signaling pathways. The aim of the present study was to investigate the perception mechanism of cultured Nicotiana tabacum cells towards LPS from Burkholderia cepacia (LPS(B.cep.)), with regard to the role of protein phosphorylation during signal perception-related responses to gain a better understanding of the chemosensory perception of LPS elicitor signals in plant cells. In vivo labeling of protein phosphorylation events during signal transduction indicated the rapid phosphorylation of several proteins with the hyperphosphorylation of two proteins of 28 and 2 kDa, respectively. Significant differences and de novo LPS-induced phosphorylation were also observed with two-dimensional analysis. The protein kinase inhibitor, staurosporine, totally inhibited the extracellular alkalinization response induced by LPS(B.cep.), while the oxidative burst was only partially inhibited by staurosporine. Inhibition of protein phosphatase activity by calyculin A intensified the LPS(B.cep.) responses. The results indicate that perception- and signal transduction responses during LPS(B.cep.) elicitation of tobacco cells require a balance between the actions of certain protein kinases and protein phosphatases.  相似文献   

20.
Both growth factor directed and integrin dependent signal transduction were shown to take place directly after completion of mitosis. The local activation of these signal transduction cascades was investigated in early G1 cells. Interestingly, various key signal transduction proteins were found in blebs at the cell membrane within 30 min after mitosis. These membrane blebs appeared in round, mitotic-like cells and disappeared rapidly during spreading of the cells in G1 phase. In addition to tyrosine-phosphorylated proteins, the blebs contained also phosphorylated FAK and phosphorylated MAP kinase. The formation of membrane blebs in round, mitotic cells before cell spreading is not specific for mitotic cells, because similar features were observed in trypsinized cells. Just before cell spreading also these cells exhibited membrane blebs containing active signal transduction proteins. Inhibition of signal transduction did not affect membrane bleb formation, suggesting that the membrane blebs were formed independent of signal transduction.  相似文献   

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