NF-κB信号通路基本元件调节机制的研究进展

核因子-kappaB（NF-κB）信号通路广泛参与调节免疫反应、炎症反应、细胞分化与凋亡、肿瘤形成等多种生物学功能。在非激活细胞中,NF-κB转录因子通常与其抑制物结合形成复合物,并在胞浆与胞核间达到平衡,但这种复合物主要存在于胞浆中。当受到胞外信号刺激后,复合物可以在NF—κB信号通路的多个信号转导途径中发生降解,使得抑制物从复合物中解离,释放出的大量活性NF—κB迅速转移入核,从而调控相应靶基因的表达。目前发现的和NF—κB的调节紊乱有关的疾病谱在不断扩大,这也使得对于NF—κB信号通路功能和调节的研究得到了深入发展,对通路中一些基本元件的调节也有了较为充分的了解。     

NBD多肽的临床应用研究进展

核因子 κB(nuclearfactor κB ,NF κB )在免疫应答、炎症反应和细胞凋亡的过程中发挥着重要作用 ,已经成为相关疾病治疗的新靶点。NF κB必需调节蛋白结合区 (NF κBessentialmodifierbindingdomain ,NBD)多肽是仅有 6个氨基酸残基的小分子肽 ,它可以与IκB激酶 (IKK)的调节亚基 (NF κBessentialmodifier ,NEMO)结合 ,阻止IKK激活 ,从而选择性地抑制NF κB的过度表达。将对许多炎症性疾病、免疫性疾病和肿瘤的治疗起到重要作用。     

Nod样受体与Toll受体介导炎症的研究进展

固有免疫系统是抵御微生物入侵的第一道防线,它依赖模式识别受体识别外源病原微生物然后将其清除。Toll样受体（TLR）和Nod样受体（NLR）是介导免疫识别的重要受体,其通过识别病原体相关分子模式不仅启动了固有免疫应答,而且激活了适应性免疫应答,是连接固有免疫和适应性免疫的桥梁。中性粒细胞是机体早期炎症反应中最重要的炎症细胞,其粘附、活化及凋亡的整个过程可受TLR的调节,促成炎症反应的无损伤性收敛,使机体维持内环境的稳态。     

人类Toll样受体信号转导途径及其介导的免疫作用

人类Toll样受体（TLR）是近年来发现的一类新的细胞表面信号传导跨膜受体,是人体固有免疫和适应性免疫的桥梁。TLR4组织分布较广泛,激活后通过TLR4-NF-κB信号途径促进细胞因子合成、激活T细胞、调节Th1／Th2免疫反应的平衡,从而调节机体的免疫状态。进一步研究TLR4的信号转导途径及其在疾病发展过程中的表达情况,可以为临床预防和治疗疾病提供新的思路和方法。     

大花旋覆花内酯通过抑制NF—κB活化抗血管炎症反应水

目的：以离体培养的血管环为研究对象，探讨大花旋覆花内酯（1-O-acetylbritannilactone，ABL）抑制脂多糖（LPS）诱导的血管炎症反应效应和分子机制。方法：将体外培养的血管环预先用ABL孵育后，再用LPS刺激，提取组织总蛋白进行Western blotting分析。结果：ABL抑制LPS诱导的IKK磷酸化活化和由此引发的IκBα的磷酸化降解，降低NF—κB水平，进而抑制NF—κB依赖的炎症因子iNOS、COX-2、ICAM-1和VCAM-1的表达。结论：ABL是一种调节NF—κB活性的制剂，具有抑制致炎因子表达，上调抑炎因子水平，维持两者平衡的作用，可消除LPS诱导的血管炎症反应     

Toll样受体在机体抗病毒免疫反应中的作用

哺乳动物的Toll样受体(TLR)家族具有模式识别受体的功能,其可以识别微生物的保守分子成分,启动机体的固有免疫系统,从而帮助机体清除病原体.利用TLR敲除的动物或细胞模型进行的研究使人们认识到TLR在机体抗病毒免疫反应中发挥着重要作用.病毒与宿主细胞的TLR结合后,通过NF-κB或IRF-3的信号路径激活细胞因子的表达,从而激发免疫应答.研究TLR如何与病原体结合及如何激活下游基因对深入认识病原体所致相关疾病的发病机制、免疫应答及病理生理具有重要的意义,并为病毒性疾病的临床治疗或免疫预防提供新的思路.     

MAPKKK与TLR信号转导研究进展

Toll样受体（TLRs）是一类模式识别受体,该家族成员可选择性识别保守的微生物成分（如细菌脂多糖、病毒双链RNA）而启动天然免疫并调节获得性免疫,因此,TLR在宿主的免疫识别与免疫应答调控中具有重要作用。TLR可激活一系列的信号转导通路,其中包括丝裂原激活的蛋白激酶（MAPK）家族和NF—κB通路。MAPK信号通路的激活调控了一系列的细胞活动,在细胞的增殖、分化、凋亡等过程中起着重要的作用。越来越多的研究表明,中间分子MAPKKK（MAP3K）在不同的细胞或在不同的细胞外刺激下激活不同的MAPK信号途径。     

核因子-κB p65在宫颈癌中的表达及意义

目的探讨核因子-κB（NF—κB）p65在宫颈癌组织中表达的意义。方法应用免疫组织化学方法检测NF—κBp65在32例宫颈癌（研究组）及30例正常宫颈组织（对照组）中的表达情况。结果宫颈癌中NF—κBp65蛋白阳性表达率为68．7％．30例正常宫颈组织中NF—κB无阳性表达，两组间比较差异具有显著性意义（P〈0．05）。结论NF—κB活化在宫颈癌的发生发展中起重要作用。     

Toll样受体调节中性粒细胞免疫作用的研究进展

Toll样受体（TLR）是固有免疫系统中特异的I型跨膜受体及病原模式识别受体。TLR能特异地识别病原体相关分子模式（PAMP）,构成机体抵御病原微生物的第一道防线,因而在固有免疫系统中发挥重要作用,而且TLR还能调节适应性免疫,是连接固有免疫和适应性免疫的桥梁。中性粒细胞（PMN）是机体最重要的炎性细胞,在固有免疫中扮演着十分重要的角色,对炎症的发生、发展及转归起了关键的作用。作为重要受体的TLR能诱导PMN的生存与活化,在急性炎症反应、细胞信号转导和细胞凋亡中起着重要作用。     

NF-κB 激活蛋白2(NAP2)诱导白细胞介素-12分泌的研究

目的：研究新克隆的编码NF—κB激活蛋白2(NAP2)基因的功能及作用机制。方法：采用NF-κB和IL—12启动子荧光素酶报告质粒及胞质内IL—12染色法，观察NAP2基因产物在巨噬细胞中对NF—κB、IL—12启动子的激活及对IL-12合成的调控。结果：NAP2可激活NF—κB和IL—12启动子，而IκBαDN则可抑制他们的活化。在巨噬细胞系J774中，NAP2也可诱导IL—12表达。结论：NAP2基因产物可激活IL—12启动子并诱导IL—12的合成，提示NAP2可能是通过调控NF—κB转录因子而调节IL—12的表达。     

Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line

Radiation therapy is a widely used cancer treatment and pre-transplantation conditioning regimen that has the potential to influence anti-tumor and post-transplantation immune responses. Although conventionally fractionated radiation doses can suppress immune responses by depleting lymphocytes, single high doses of local tumor radiation can enhance immune responses. Using phospho-flow cytometry analysis of a human monocytic cell line, we identified novel radiation-induced changes in the phosphorylation state of NFκB family members known in other cell types to maintain and regulate immune function. These phosphorylation changes were p53 independent, but were strongly dependent upon ATM activation due to DNA damage. We found that radiation promotes the activation and APC functional maturation through phosphorylation of NFκB Essential Modulator (NEMO). Our results and the analytic methods are especially well suited to the study of functional changes in APC when radiation is used for immune modulation in clinical protocols.     

Apigenin inhibits release of inflammatory mediators by blocking the NF-κB activation pathways in the HMC-1 cells

Apigenin is a plant flavonoid and a pharmacologically active agent that has been isolated from several plant species. However, the molecular mechanism of apigenin-mediated immune modulation has not been fully understood. One of the possible mechanisms of its protective effects is the down-regulation of inflammatory responses. In this study, we used cells from the human mast cell line (HMC-1) to investigate this effect. Apigenin significantly inhibits the inductive effect of phorbol 12-myristate 13-acetate (PMA) plus A23187 on the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, apigenin attenuated the cyclooxygenase (COX)-2 expression and intracellular Ca(2+) level. In activated HMC-1 cells, apigenin inhibited the PMA plus A23187-induced activation of nuclear factor (NF)-κB, IκB degradation, and luciferase activity. Furthermore, apigenin suppressed the expression of TNF-α, IL-8, IL-6, GM-CSF, and COX-2 by decreasing the intracellular Ca(2+) level and inhibiting NF-κB activation. These results indicate that apigenin has a potential regulatory effect on inflammatory reactions that are mediated by mast cells.     

Control of NF-κB and inflammation by the unfolded protein response

Under inflammatory situations, endoplasmic reticulum (ER) stress occurs at local sites and modulates inflammatory processes. NF-κB is a key regulator for immune and inflammatory responses, and its activity is influenced by ER stress positively or negatively. Recent investigation suggested that ER stress induces activation of NF-κB in the early phase, whereas in the later phase, consequent unfolded protein response (UPR) inhibits NF-κB. This review summarizes current knowledge on potential mechanisms underlying the biphasic, bidirectional regulation of NF-κB by the UPR and possible roles for ER stress in the regulation of inflammation.     

Role of NF-κB in epithelial biology

Since its discovery, nuclear factor-κB (NF-κB) has been recognized as a critical regulator of immune responses. While early studies focused on studying the role of NF-κB in the development and function of immune cells, more recently the function of the inhibitor of NF-κB kinase (IKK)/NF-κB pathway in non-immune cells has gained increased attention. Studies in genetic mouse models were instrumental in dissecting the cell-specific functions of NF-κB and provided experimental evidence that NF-κB signaling in epithelial cells is important for the maintenance of immune homeostasis in barrier tissues such as the skin and the intestine. Increased activation of IKK/NF-κB triggered cytokine expression by the epithelial cells, resulting in exacerbated tissue inflammatory responses. NF-κB inhibition in keratinocytes triggered severe tumor necrosis factor-dependent skin inflammation and epidermal hyperplasia, while inhibition of IKK/NF-κB signaling in intestinal epithelial cells disturbed the intestinal barrier and triggered severe chronic colon inflammation. Therefore, epithelial NF-κB signaling performs critical 'peace keeping' functions in barrier tissues at the interface with the environment by regulating cell survival, barrier integrity, and the immunological and anti-microbial responses of epithelial cells. Improved understanding of epithelial NF-κB functions may hold the key for elucidating the etiology and pathophysiology of chronic inflammatory diseases in epithelial tissues.