查看胞壁酰二肽及其衍生物:免疫疾病和癌症治疗中的肽佐剂的源代码
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胞壁酰二肽及其衍生物:免疫疾病和癌症治疗中的肽佐剂
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=== 作用机制 === Nod2:MDP 受体及其信号转导 MDP 及其衍生物被病原体识别受体分子 NOD2(CARD15)特异性识别,该分子通过调节细胞因子、趋化因子和抗菌肽的产生,在适应性和先天性免疫系统中发挥作用[40–44]。NOD2 属于 NLR(核苷酸结合结构域-富含亮氨酸的重复序列)蛋白家族,具有三个基序:(1) 含有半胱天冬酶募集结构域 (CARD) 的 N 末端效应结构域;(2)NBD(核苷酸结合域),具有ATP结合位点,是寡聚化所必需的;(3)富含亮氨酸重复序列(LRR)结构域[45‒48]。它在参与宿主防御的几种细胞类型的细胞质中表达,包括巨噬细胞、树突状细胞、外周血单核细胞和肠上皮细胞(尤其是潘氏细胞)[42,49–52]。 在北美和欧洲人群中,30%-40% 的克罗恩病患者发现了 NOD2 内的3个突变[52,53]。炎症性肠病(IBD),如克罗恩病(Crohn's disease, CD),是由遗传、表观遗传和环境因素导致慢性激活的免疫系统细胞因子产生过多[54–58]。IBD1 位点的定位导致发现了编码在人类染色体 16q12 上的 NOD2,这是第一个与 CD 相关的基因[52,53]。所有三个 CD 相关突变都局限于或位于蛋白质 C 末端的 LRR 结构域附近。虽然 3020insC 移码突变导致过早终止密码子部分截断 LRR 结构域,但 R702W 和 G908R 突变体是单核苷酸多态性(SNP)[59,60]。NOD2 基因突变如何导致 CD 的确切机制尚不完全清楚。提出的假设包括 Toll 样受体信号失调导致的免疫反应改变或潘氏细胞功能缺陷,潘氏细胞通过抗菌化合物调节共生菌和致病菌[42,61–65]。 Nod2: MDP receptor and its signaling MDP and its derivatives are specifically recognized by the pathogen recognition receptor molecule NOD2 (CARD15) that plays a role in both adaptive and innate immune systems by regulating cytokine, chemokine, and antimicrobial peptide production [40–44]. NOD2 belongs to the NLR (nucleotide binding domain-leucine rich repeats) protein family and is characterized by three motifs: (1) An N-terminal effector domain containing a caspase recruitment domain (CARD); (2) An NBD (nucleotide binding domain), which has a binding site for ATP and is required for oligomerization; and (3) A leucine rich repeats (LRR) domain [45–48]. It is expressed in the cytoplasm of several cell types involved in host defense, including macrophages, dendritic cells, peripheral blood mononuclear cells, and intestinal epithelial cells (especially Paneth cells) [42, 49–52]. Three mutations within NOD2 have been identified in 30 – 40% of Crohn’s Disease patients in North American and European populations [52, 53]. Inflammatory bowel diseases (IBDs) such as Crohn’s Disease (CD) are due to genetic, epigenetic, and environmental factors leading to the overproduction of cytokines from a chronically activated immune system [54–58]. Mapping of the IBD1 locus has led to the discovery of NOD2 encoded on human chromosome 16q12 as the first gene linked to CD [52, 53] . All three CD-associated mutations are restricted to or are in the vicinity of the LRR domain located in the C-terminus of the protein. While the 3020insC frameshift mutation results in a premature stop codon that partially truncates the LRR domain, the R702W and G908R mutants are single nucleotide polymorphisms (SNPs) [59, 60]. The precise mechanism underlying how mutations in the NOD2 gene cause CD is not yet fully understood. Proposed hypotheses include an altered immune response by dysregulated Toll-like receptor signaling or a defective function of Paneth cells, which regulate commensal and pathogenic bacteria thorough antimicrobial compounds [42, 61–65]. MDP刺激的信号级联反应 检测到MDP后,NOD2通过CARD-CARD同亲性相互作用与激酶RIP2结合,这是下游信号转导进行所必需的步骤[66‒68]。RIP2的信号转导通过IKK(IkB激酶)复合物以及涉及MAP激酶的其他级联反应导致NF-kB转录活性,从而产生促炎细胞因子和趋化因子,如白细胞介素-6(IL-6)、肿瘤坏死因子-a(TNF-α)、IL-12和IL-8(图2)[42,69,70]。 图2 有几种蛋白质可以调节NOD2信号转导,包括Erbin[58,71–74]。目前,已经表明Erbin通过其CARD与蛋白质结合,从而抑制其在MDP刺激下诱导NF-kB活性的能力,从而作为NOD2的负调节因子[58,73]。NOD2 和 RIP2 还通过 IL-1β 和 IL-18 的半胱天冬酶-1 依赖性成熟参与细胞死亡和炎症的调节。体外和体内研究表明,在MDP刺激下,NOD2和RIP2都是Caspase-1激活和IL-1β产生所必需的[75]。 Signaling cascades of MDP stimulation Upon detection of MDP, NOD2 binds to the kinase RIP2 via CARD-CARD homophilic interactions, a step required in order for downstream signaling to proceed [66–68]. Signaling to RIP2 leads to NF-kB transcriptional activity through the IKK (IkB kinase) complex as well as other cascades involving MAP kinases that result in the production of pro-inflammatory cytokines and chemokines such as interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), IL-12, and IL-8 (Fig. 2) [42, 69, 70]. Several proteins are postulated to regulate NOD2 signaling, including Erbin [58, 71–74]. Currently, it has been shown that Erbin serves as a negative regulator of NOD2 by binding to the protein via its CARDs and thus inhibiting its ability to induce NF-kB activity upon MDP stimulation [58, 73]. NOD2 and RIP2 are also involved in the regulation of cell death and inflammation through the caspase-1-dependent maturation of IL-1β and IL-18. It has been shown in vitro and in vivo that upon MDP stimulation NOD2 and RIP2 are both required for Caspase-1 activation and IL-1β production [75]. <br>
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