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yaoguiyang木蟲 (小有名氣)
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| Inappropriate activation of Toll-like receptors（TLRs）, on the other hand, contributes to development of a variety of human diseases including systemic lupus erythematosus (SLE), bacterial sepsis, inflammatory bowel disease, psoriasis, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. Upon infection or injury of tissue, the infected or damaged tissue releases various intracellular factors that can recruit and activate innate immune cells. Nucleic acids that originate from host cells or intracellular microorganisms can be recognized by nucleic acid-sensing TLRs and can result in the induction of pathological inflammatory responses . In patients with bacterial sepsis, toxic shock, SLE or rheumatoid arthritis, hypomethylated CpG DNAs, or RNAs have been detected in extracellular compartments and these extracellular nucleic acids have been correlated to the pathogenesis of these diseases. Although inhibition of one or two nucleic acid-sensing TLRs using receptor antagonists has been demonstrated to attenuate disease progression in polymicrobial sepsis and autoimmune disease models to some extent, the redundancy of the TLR family of proteins suggests that concurrent inhibition of all nucleic acid-sensing TLRswould be the most effective means to control nucleic acid-induced inflammation in humans. Because all the nucleic acid-sensing TLRs bind to RNA or DNA, albeit each TLR ligand contains a distinguishable molecular pattern, we hypothesized that agents that bind to DNAs and RNAs regardless of their sequence, structure or chemistry might be able to inhibit nucleic acid-mediated activation of all RNA- and DNA-sensing TLRs. Herein we demonstrate that certain cationic polymers can act as molecular scavengers and block the immune stimulatory effects of extracellular ssRNA, dsRNA, and unmethylated DNA. Nucleic Acid-Binding Polymers Inhibit Nucleic Acid-Mediated Activation of TLRs. We initially evaluated six agents known to bind nucleic acids for their ability to attenuate nucleic acid-mediated activation of TLRs on macrophages: polyphosphoramidate polymer (PPA-DPA), polyamidoamine dendrimer, 1,4-diaminobutane core-PAMAM-G3 (PAMAM-G3), poly-L-lysine, β-cyclodextrincontaining polycation (CDP), hexadimethrine bromide (HDMBr), and protamine sulfate. All of the compounds except protamine sulfate inhibit TLR3 activation by synthetic dsRNA, polyinosinic-polycytidylic acid (poly I∶C) as measured by TNFα and IL-6 production and CD80 expression.Moreover three of the cationic polymers, CDP, HDMBr, and PAMAM-G3 inhibit the ability of synthetic CpG DNAs (CpG 1668) to activate TLR9. Similarly these three polymers inhibit the ability of ssRNA-lipid complexes (ssRNA40) to activate TLR7. Such cationic polymers are specific for nucleic acid-mediated activation of the TLRs. They do not inhibit activation of TLRs that recognize nonnucleic acid-based TLR agonists such as bacterial LPS, which activate TLR4, and Pam3CSK4, a synthetic bacterial lipoprotein, which activates the TLR2/1 complex. Furthermore CDP, HDMBr, and PAMAM-G3 neutralize immune stimulatory activity of all types of nucleic acid-based TLR agonists in a variety of primary cells including B cells, fibroblasts and dendritic cells (DCs) |
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QQ905063299 
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reko34
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yaoguiyang: 金幣+60, 翻譯EPI+1, ★★★★★最佳答案 2014-06-20 12:41:46
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| 另一方面，Toll樣受體的不恰當(dāng)激活有助于各種人體疾病的發(fā)展，包括系統(tǒng)性紅斑狼瘡(SLE)、細(xì)菌性敗血癥、炎性腸道疾病、銀屑病、多發(fā)性硬化、類風(fēng)濕性關(guān)節(jié)炎和動(dòng)脈粥樣硬化。組織感染或受傷時(shí)，感染或受損組織釋放出各種能吸引和激活先天性免疫細(xì)胞的細(xì)胞因子。來(lái)自宿主細(xì)胞或細(xì)胞內(nèi)微生物的核酸能被核酸感知的TLRs識(shí)別，可能導(dǎo)致誘發(fā)病理性炎癥反應(yīng)。在有細(xì)菌性敗血癥、中毒性休克、SLE或類風(fēng)濕關(guān)節(jié)炎的病人的細(xì)胞間隔中發(fā)現(xiàn)低甲基化CpGDNA或RNA，這些細(xì)胞外核酸與疾病的發(fā)病有關(guān)。盡管在多細(xì)菌敗血癥和自身免疫性疾病模型中，用受體拮抗劑抑制一兩種核酸感知的TLRs經(jīng)證明能在一定程度上衰減疾病發(fā)展，TLR蛋白家族的過(guò)剩顯示，同時(shí)抑制所有核酸感知的TLRs是控制人體中核酸誘發(fā)炎癥的最有效方式。由于所有的核酸感知TLRs都結(jié)合RNA或DNA，盡管每種TLR配體含有可分辨的分子模式，我們假設(shè)與DNAs和RNAs結(jié)合的成分也許能抑制以核酸為媒介的所有RNA和DNA感知TLRs的激活，不論其順序、結(jié)構(gòu)或化學(xué)。于是我們證實(shí)，特定的陽(yáng)離子聚合物能充當(dāng)分子清道夫，阻斷細(xì)胞外ssRNA、dsRNA和未甲基化DNA的免疫刺激作用。結(jié)合核酸的聚合物抑制以核酸為媒介的TLRs激活。我們最初評(píng)價(jià)巨噬細(xì)胞中6種已知結(jié)合核酸并能減弱以核酸為媒介的TLRs激活的成分：聚氨基磷酸酯聚合物(PPA-DPA)、聚酰胺-胺樹狀大分子、1,4-二氨基丁烷芯PAMAM-G3(PAMAM-G3)、聚-L-賴氨酸、β-環(huán)糊精的聚陽(yáng)離子(CDP)、溴化己二甲（HDMBr）和硫酸魚精蛋白。通過(guò)TNFα和IL-6產(chǎn)物的測(cè)量及CD80表現(xiàn)度，除硫酸魚精蛋白外的所有成分都阻礙TLR3被合成dsRNA、聚肌胞苷酸(poly I∶C)激活。此外，3種陽(yáng)離子聚合物，CDP、HDMBr和PAMAM-G3阻礙合成CpG DNAs（CpG 1668）激活TLR9。類似地，這3種聚合物阻礙ssRNA-脂質(zhì)復(fù)合物（ssRNA40）激活TLR7。這類陽(yáng)離子聚合物在以核酸為媒介的TLRs激活中是特例。它們不抑制識(shí)別非基于核酸的TLR激動(dòng)劑——如細(xì)菌LPS、Pam3CSK4、合成細(xì)菌脂蛋白、TLR2/1復(fù)合物——的TLRs的激活。此外，CDP、HDMBr和PAMAM-G3在各種原代細(xì)胞包括B細(xì)胞、成纖維細(xì)胞和樹突狀細(xì)胞（DCs）內(nèi)中和各類基于核酸的TLR激動(dòng)劑的免疫刺激活性。 |
3樓2014-06-20 11:30:18
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