Endotoxin up-regulates interleukin-18 - Potential role for gram-negative colonization in sarcoidosis
Endotoxin up-regulates interleukin-18 - Potential role for gram-negative colonization in sarcoidosis
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DOI：
10.1164/rccm.200411-1594oc
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发表时间：
2005-11-15
影响因子：
24.7
通讯作者：
McElvaney, NG
中科院分区：
文献类型：
--
作者：
Kelly, DM;Greene, CM;McElvaney, NG
理论基础和目的：结节病是一种病因不明的肉芽肿性疾病，其特征是辅助性T细胞1型介导的过程。在此之前，我们展示了白细胞介素18在结节病中的作用。在此，我们研究了白介素18在这种情况下的调节。方法：用双抗体夹心法测定结节上皮衬衬液中的细胞因子水平。我们检测了活动性结节病患者和结节病康复者上皮衬壁液中IL-18启动子的活性以及对结核分枝杆菌、硫酸铍、硫酸锆、硫酸铝和脂多糖纯化蛋白衍生物的反应。对结节病患者、结节病康复者和对照组的上皮衬里液中的内毒素水平进行了分析。采用等位基因特异性聚合酶链式反应技术，对94例结节病患者和97例对照组的白细胞介素18-607(A/C)基因多态性进行了基因分型。结果：与恢复期患者相比，活动期结节上皮衬里液中IL-18、干扰素-γ和IL-12水平升高，内毒素水平也明显升高。在体外，去除这种上皮衬里液体中的包膜毒素会降低其对人白介素18启动子的影响。与对照组相比，结节病组人群中-607(C)等位基因和-607(C/C)基因型的频率较高；然而，这与对包涵体毒素治疗的功能性反应无关。在结节样液标本中检测到流感嗜血杆菌和卡他莫拉菌的细菌16S rRNA。结论：结节病的发病机制是通过辅助性T细胞1型驱动的反应而传播的。这项研究表明，革兰氏阴性细菌可能通过上调白细胞介素18的表达来起到这种作用。
Rationale and Objectives: Sarcoidosis is a granulomatous disease of unknown etiology characterized by a helper T-cell type 1-mediated process. Previously we demonstrated a role for interleukin-18 in sarcoidosis. Here we examine the regulation of interleukin-18 in this condition.Methods: Cytokine levels in sarcoid epithelial lining fluid were measured by ELISA. We examined interleukin-18 promoter activity and mRNA and protein levels in the epithelial lining fluid of individuals with active sarcoidosis, and of individuals recovered from sarcoidosis, in response to purified protein derivative of Mycobacterium tuberculosis, beryllium sulfate, zirconium sulfate, aluminum sulfate, and lipopolysaccharide. Endotoxin levels in the epithelial lining fluid of individuals with sarcoidosis, individuals recovered from sarcoidosis, and control subjects were assessed by Limulus amebocyte lysate analysis. Allele-specific polymerase chain reaction was used to genotype 94 patients with sarcoiclosis and 97 control subjects for the interleukin-18 -607(A/C) polymorphism. Species-specific polymerase chain reaction identified bacterial DNA in fluid samples.Results: Epithelial lining fluid from active sarcoids contained elevated levels of interleukin-18, interferon-gamma, and interleukin-12 compared with recovered patients and also contained significantly higher levels of endotoxin. Depletion of enclotoxin from this epithelial lining fluid reduced its effect on the human interleukin-18 promoter in vitro. There was a higher frequency of the -607(C) allele and -607(C/C) genotype in the sarcoiclosis population compared with control subjects; however, this was not associated with a functional response to enclotoxin treatment. Finally, bacterial 16S rRNA from Haemophilus influenzae and Moraxella catarrhalis was detected in sarcoid fluid samples.Conclusions: The pathogenesis of sarcoiclosis is propagated through the actions of a helper T-cell type 1-driven response. This study shows that gram-negative bacteria may contribute to this effect by upregulating interleukin-18 expression.