In vitro evaluation of the immunotoxic potential of perfluorinated compounds (PFCs)
In vitro evaluation of the immunotoxic potential of perfluorinated compounds (PFCs)
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DOI：
10.1016/j.taap.2010.11.004
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发表时间：
2011-01-15
影响因子：
3.8
通讯作者：
Germolec, Dori R.
中科院分区：
文献类型：
--
作者：
Corsini, Emanuela;Avogadro, Anna;Germolec, Dori R.
流行病学和实验室研究都有证据表明，全氟化合物可能具有免疫毒性，影响细胞免疫和体液免疫。本研究的总体目标是通过体外实验研究全氟辛烷磺酸（PFOS）和全氟辛烷酸（PFOA）免疫毒性作用的机制。在脂多糖（LPS）刺激的人外周血白细胞和早幼粒细胞细胞系THP-1中评估促炎细胞因子IL-6、IL-8和tnf - α的释放，而在植物血凝素（PHA）刺激的外周血白细胞中评估IL-4、IL-10和ifn - γ的释放。PFOA和PFOS抑制lps诱导的人原代培养物和THP-1细胞中TNF-a的产生，而IL-8仅在THP-1细胞中受到抑制。IL-6释放仅被PFOS降低。PFOA和PFOS均能降低t细胞来源的、pha诱导的IL-4和IL-10的释放，而ifn - γ的释放仅受PFOS的影响。在所有情况下。全氟辛烷磺酸比全氟辛烷磺酸更有效。在THP-1细胞中进行的机制研究表明，通过lps诱导的TNF-a mRNA表达减少，对细胞因子释放的影响是转录前的。利用siRNA可以证明PPAR-a在pfoa诱导的免疫毒性中起作用，而对lps诱导的I-NB降解的抑制作用可以解释PFOS的免疫调节作用。PPAR-a在PFOA和PFOS诱导的免疫毒性中的不同作用与lps诱导的MMP-9释放的不同作用是一致的：PFOA作为PPAR-a激动剂非诺贝特调节MMP-9的释放，而PFOS没有影响。综上所述，这些研究表明pfc直接抑制免疫细胞的细胞因子分泌，PFOA和PFOS具有不同的作用机制。(C) 2010爱思唯尔公司版权所有。
There is evidence from both epidemiology and laboratory studies that perfluorinated compounds may be immunotoxic, affecting both cell-mediated and humoral immunity. The overall goal of this study was to investigate the mechanisms underlying the immunotoxic effects of perfluorooctane sulfonate (PFOS) and perfluorooctane acid (PFOA), using in vitro assays. The release of the pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha was evaluated in lipolysaccharide (LPS)-stimulated human peripheral blood leukocytes and in the human promyelocytic cell line THP-1, while the release of IL-4, IL-10 and IFN-gamma was evaluated in phytohaemagglutinin (PHA)-stimulated peripheral blood leukocytes. PFOA and PFOS suppressed LPS-induced TNF-a production in primary human cultures and THP-1 cells, while IL-8 was suppressed only in THP-1 cells. IL-6 release was decreased only by PFOS. Both PFOA and PFOS decreased T-cell derived, PHA-induced IL-4 and IL-10 release, while IFN-gamma release was affected only by PFOS. In all instances. PFOS was more potent than PFOA. Mechanistic investigations carried out in THP-1 cells demonstrated that the effect on cytokine release was pre-transcriptional, as assessed by a reduction in LPS-induced TNF-a mRNA expression. Using siRNA, a role for PPAR-a could be demonstrated for PFOA-induced immunotoxicity, while an inhibitory effect on LPS-induced I-NB degradation could explain the immunomodulatory effect of PFOS. The dissimilar role of PPAR-a in PFOA and PFOS-induced immunotoxicity was consistent with the differing effects observed on LPS-induced MMP-9 release: PFOA, as the PPAR-a agonist fenofibrate, modulated the release, while PFOS had no effect. Overall, these studies suggest that PFCs directly suppress cytokine secretion by immune cells, and that PFOA and PFOS have different mechanisms of action. (C) 2010 Elsevier Inc. All rights reserved.