Glycogen synthase kinase-3beta (GSK3beta) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice.
Glycogen synthase kinase-3beta (GSK3beta) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice.
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DOI：
10.1016/j.molimm.2008.08.281
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发表时间：
2009-02
影响因子：
3.6
通讯作者：
Michalek, Suzanne M.
中科院分区：
文献类型：
--
作者：
Zhang, Ping;Katz, Jenny;Michalek, Suzanne M.
土拉热弗朗西斯菌是土拉菌病的病原体，由于其高毒力，目前被认为是A类生物恐怖主义制剂。感染F.土拉热导致炎症反应，其在疾病的发病机制中起重要作用;然而，调节该反应的细胞机制知之甚少。糖原合成酶激酶-3 β（GSK 3 β）是一种丝氨酸/苏氨酸蛋白激酶，最近成为调节炎症反应的关键调节开关。本研究探讨了抑制GSK 3 β对F.土拉热LVS诱导的炎症反应。F. tularensis LVS感染小鼠腹腔巨噬细胞诱导TLR 2依赖的GSK 3 β磷酸化。抑制GSK 3 β导致促炎细胞因子IL-6、IL-12 p40和TNF-α的产生显著减少，抗炎细胞因子IL-10的产生显著增加。GSK 3 β调节F.土拉菌通过差异影响转录因子NF-κB和CREB的活化诱导细胞因子应答。锂在体内抑制GSK 3 β可抑制F. tularensis LVS，并赋予生存优势。此外，我们表明，IFN-γ的产生有助于兔热病的发展和感染动物的致命结果，这取决于IFN-γ产生的时间和相对水平。IFN-γ增强F.土拉菌通过增加GSK 3 β活性和NF-κB核转位诱导细胞因子产生。综上所述，这些结果证明了GSK 3 β在调节炎症反应中的调节功能，该炎症反应在F. Tularensis LVS感染，并提示抑制GSK 3 β可能代表治疗土拉菌病的新治疗方法。
Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3β inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3β. Inhibition of GSK3β resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-α, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3β regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-κB and CREB. Inhibition of GSK3β by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-γ contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-γ produced. IFN-γ potentiated F. tularensis LVS-induced cytokine production by increasing GSK3β activity and the nuclear translocation of NF-κB. Taken together, these results demonstrate a regulatory function of GSK3β in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3β may represent a novel therapeutic approach in the treatment of tularemia.
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