Early gene expression changes induced by the bacterial superantigen staphylococcal enterotoxin B and its modulation by a proteasome inhibitor
Early gene expression changes induced by the bacterial superantigen staphylococcal enterotoxin B and its modulation by a proteasome inhibitor
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DOI：
10.1152/physiolgenomics.90385.2008
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发表时间：
2009-05-01
影响因子：
4.6
通讯作者：
David, Chella S.
中科院分区：
文献类型：
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作者：
Rajagopalan, Govindarajan;Tilahun, Ashenafi Y.;David, Chella S.
Rajagopalan G，Tilahun AY，Asmann YW，大卫CS.细菌超抗原葡萄球菌肠毒素B诱导的早期基因表达变化及其蛋白酶体抑制剂的调节Physiol Genomics 37：279-293，2009.首次发表于2009年3月31日; doi：10.1152/physiolgenomics.90385.2008。中毒性休克综合征（TSS）是由细菌超抗原引起的急性、严重的全身性疾病。直到最近，一个合适的动物模型的不可用性阻碍了深入了解TSS的发病机制。在目前的研究中，我们使用我们的HLA-DR 3转基因小鼠模型的TSS的早期分子事件的特点。使用DNA微阵列的基因表达谱鉴定了几种促炎和抗炎介质的快速和显著的上调，其中许多以前从未在TSS中描述过。葡萄球菌肠毒素B（SE B）的体内给药导致Th 0-（IL-2，240倍）、Th 1（IFN-γ，360倍; IL-12，8倍）、Th 2-（IL-4，53倍; IL-5，4倍）以及Th 17型细胞因子（IL-21，19倍; IL-17，5倍）的表达增加。免疫调节细胞因子（IL-6，700倍; IL-10，18倍）; CC趋化因子（如CCL 2，11，3，24，17，12，7），CXC趋化因子（如CXCL 1，2，5，11，10，19）;和几种蛋白酶（基质金属蛋白酶13，8，3和9）也被上调。这些细胞因子/趋化因子中的几种的血清水平也显著升高。通路分析揭示了多种生化和细胞功能的显著调节，为TSS的发病机制提供了分子见解。硼替佐米（一种临床批准的蛋白酶体抑制剂，能够阻断NF-κ B通路）的给药能够显著调节SE B诱导的多种基因的表达。因此，我们的研究表明TSS是一个复杂的过程，并强调了硼替佐米在治疗超抗原诱导的TSS中的潜力。
Rajagopalan G, Tilahun AY, Asmann YW, David CS. Early gene expression changes induced by the bacterial superantigen staphylococcal enterotoxin B and its modulation by a proteasome inhibitor. Physiol Genomics 37: 279-293, 2009. First published March 31, 2009; doi:10.1152/physiolgenomics.90385.2008.-Toxic shock syndrome (TSS) is an acute, serious systemic illness caused by bacterial superantigens. Nonavailability of a suitable animal model until recently has hampered an in-depth understanding of the pathogenesis of TSS. In the current study, we characterized the early molecular events underlying TSS using our HLA-DR3 transgenic mouse model. Gene expression profiling using DNA microarrays identified a rapid and significant upregulation of several pro-as well as anti-inflammatory mediators, many of which have never been previously described in TSS. In vivo administration of staphylococcal enterotoxin B (SEB) led to an increase in the expression of Th0- (IL-2, 240-fold); Th1(IFN-gamma, 360-fold; IL-12, 8-fold); Th2- (IL-4, 53-fold; IL-5, 4-fold) as well as Th17-type cytokines (IL-21, 19-fold; IL-17, 5-fold). The immunoregulatory cytokines (IL-6, 700-fold; IL-10, 18-fold); CC chemokines (such as CCL 2, 11, 3, 24, 17, 12, 7), CXC chemokines (such as CXCL 1, 2, 5, 11, 10, 19); and several proteases (matrix metalloproteinases 13, 8, 3, and 9) were also upregulated. Serum levels of several of these cytokines/chemokines were also significantly elevated. Pathway analyses revealed significant modulation in a variety of biochemical and cellular functions, providing molecular insights into the pathogenesis of TSS. Administration of bortezomib, a clinically approved proteasome inhibitor capable of blocking NF-kappa B pathway, was able to significantly modulate the expression of a variety of genes induced by SEB. Thus, our study showed that TSS is a complex process and emphasized the potential of use of bortezomib in the therapy of superantigen-induced TSS.