Detrimental effect of the proteasome inhibitor, bortezomib in bacterial superantigen- and lipopolysaccharide-induced systemic inflammation.
Detrimental effect of the proteasome inhibitor, bortezomib in bacterial superantigen- and lipopolysaccharide-induced systemic inflammation.
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蛋白酶体抑制剂硼替佐米对细菌超抗原和脂多糖诱导的全身炎症的有害作用。
DOI：
10.1038/mt.2010.53
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Rajagopalan,Govindarajan
中科院分区：
文献类型：
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作者：
Tilahun,AshenafiY;Theuer,JayneE;Patel,Robin;David,ChellaS;Rajagopalan,Govindarajan
细菌超抗原（BSAg）诱导的中毒性休克综合征（TSS）和细菌脂多糖（LPS）诱导的休克以严重的全身炎症为特征。由于核因子κB （NFκB）在炎症中起重要作用，而硼替佐米是一种广泛用于癌症化疗的蛋白酶体抑制剂，是一种有效的NFκB激活抑制剂，我们使用小鼠模型评估了硼替佐米在这些条件下的治疗和预防使用。硼替佐米预防显著降低BSAg诱导的许多细胞因子和趋化因子的血清水平。然而，在3小时时，血清中与TSS有关的重要细胞因子TNF-a水平显著降低，但未完全消除。在6小时时，硼替佐米治疗和未治疗的葡萄球菌肠毒素B （SEB）小鼠的血清TNF-a水平没有差异。矛盾的是，在BSAg攻击之前或之后接受硼替佐米治疗的所有小鼠都屈服于TSS。如果单独给药，硼替佐米和BSAg都不是致命的。血清生化指标和组织病理学结果提示急性肝功能衰竭可能是死亡的原因。硼替佐米处理的seb小鼠肝组织显示NFκB活化显著降低。由于nf - κ b依赖的抗凋亡通路保护肝细胞免受TNF-α-诱导的细胞死亡，因此在BSAg或LPS引起TNF-α水平升高时，硼替佐米抑制nf - κ b是有害的。
Bacterial superantigen (BSAg)–induced toxic shock syndrome (TSS) and bacterial lipopolysaccharide (LPS)–induced shock are characterized by severe systemic inflammation. As nuclear factor κB (NFκB) plays an important role in inflammation and bortezomib, a proteasome inhibitor widely used in cancer chemotherapy, is a potent inhibitor of NFκB activation, we evaluated the therapeutic and prophylactic use of bortezomib in these conditions using murine models. Bortezomib prophylaxis significantly reduced serum levels of many cytokines and chemokines induced by BSAg. However, at 3 hours, serum level of TNF-a, an important cytokine implicated in TSS, was significantly reduced but not abolished. At 6 hours, there was no difference in the serum TNF-a levels between bortezomib treated and untreated mice challenged with staphylococcal enterotoxin B (SEB). Paradoxically, all mice treated with bortezomib either before or after BSAg challenge succumbed to TSS. Neither bortezomib nor BSAg was lethal if given alone. Serum biochemical parameters and histopathological findings suggested acute liver failure as the possible cause of mortality. Liver tissue from SEB-challenged mice treated with bortezomib showed a significant reduction in NFκB activation. Because NFκB-dependent antiapoptotic pathways protect hepatocytes from TNF-α-induced cell death, inhibition of NFκB brought forth by bortezomib in the face of elevated TNF-α levels caused by BSAg or LPS is detrimental.