Genetic analysis of cytokine promoters in nonhuman primates: implications for Th1/Th2 profile characteristics and SIV disease pathogenesis.
Genetic analysis of cytokine promoters in nonhuman primates: implications for Th1/Th2 profile characteristics and SIV disease pathogenesis.
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DOI：
10.1080/10446670410001670472
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发表时间：
2004-03
影响因子：
--
通讯作者：
Ansari AA
中科院分区：
文献类型：
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作者：
Bostik P;Watkins M;Villinger F;Ansari AA
从原型的主要合成 Th 1型细胞因子通过抗原转化为Th 2或Th 0型细胞因子 来自HIV感染的人和SIV感染的人的活化PBMC 疾病易感的恒河猴（RM）已被证明 与疾病进展有关。巧合的是，抗原 活化的PBMC来自于白眉猴（SM），其天然地 感染了SIV，尽管病毒载量很高， 维持主要的Th 2细胞因子谱。这是有道理的 对细胞因子合成扰动的抵抗力， 和/或非进展HIV感染患者和SIV感染疾病 易感RM继发于遗传多态性， 细胞因子的启动子区域。相似启动子多态性 也可能有助于来自SM的PBMC的细胞因子谱。到 主要Th 1/Th 2细胞因子的启动子区 从RM和SM的cDNA中克隆并测序。序列分析 IL-4、IL-10、IL-12 p40、IFN-γ和IFN-γ的启动子片段的表达 来自两种猴子物种的TNF-α显示出不同程度的 同源性范围从检测到的高度同源性， IFN-γ启动子（>99%）多态性程度相对较高 检测到TNF-α启动子（94%同源性）。此外，几个 IL-12 p40、IL-10和 两个物种的TNF-α序列存在多态性 其构成已知转录因子（TF）的结合位点。等 差异可能差异地结合TF，因此 定性和/或定量地影响细胞因子的调节 这两个物种的合成， 有助于疾病进展和/或抗性。
The shift from a predominant synthesis of prototype Th1 cytokines to Th2 or Th0 type of cytokines by antigen activated PBMC's from HIV infected humans and SIV infected disease susceptible rhesus macaques (RM) has been shown to be associated with disease progression. Paradoxically, antigen activated PBMC's from sooty mangabeys (SM), which are naturally infected with SIV and are disease resistant despite high viral loads, maintain a predominant Th2 cytokine profile. It has been reasoned that the resistance to perturbations of cytokine synthesis by slow and/or nonprogressor HIV infected patients and SIV infected disease susceptible RM is secondary to inherited polymorphisms within the promoter regions for cytokines. Similar promoter polymorphisms could also contribute to the cytokine profile of PBMC's from SM. To address this issue promoter regions for the major Th1/Th2 cytokines from RM and SM were cloned and sequenced. Sequence analysis of promoter fragments of IL-4, IL-10, IL-12 p40, IFN-gamma and TNF-alpha from the two monkey species showed varying degree of homology ranging from high degree of homology detected for IFN-gamma promoter (>99%) to relatively high degree of polymorphism detected for TNF-alpha promoter (94% homology). In addition, several variable regions within the promoters of IL-12 p40, IL-10 and TNF-alpha in the two species contain polymorphisms in sequences that constitute binding sites of known transcription factors (TF). Such differences are likely to differentially bind TF and thus either qualitatively and/or quantitatively affect the regulation of cytokine synthesis in these two species and potentially contribute to disease progression and/or resistance.