鏈球菌致熱性外毒素A（streptococcal pyrogenic exotoxin A, SPEA）是由會造成致命性鏈球菌中毒性休克症候群（streptococcal toxic shock syndrome，STSS）之化膿性鏈球菌（Streptococcus pyogenes）所產生。在本篇論文中首次提出證據指出，在人類週邊單核細胞中，SPEA是透過PI3K-Akt途徑及活化NF-kB之機制，來產生會造成發燒的致熱性細胞素（pyrogenic cytokines）。以SPEA處理PBMC 12小時後，收集上清液分析IL-1及TNF細胞素的含量即可發現明顯的增加，並於SPEA處理PBMC 72小時後，IL-1及TNF的含量可達到最大量，而IL-1及TNF的產量與SPEA處理的劑量具有相關性。以西方點墨法（Western blot analysis）觀察RelA/p65從細胞質移入細胞核的表現量或以electrophoretic mobility shift assay (EMSA)觀察細胞核內NF-kB與DNA結合的能力，發現皆與SPEA處理的時間及劑量具有相關性。以SPEA處理PBMC後會活化NF-kB、造成上清液中IL-1及TNF含量增加的現象，會因為加入PI3K的抑制劑－wortmannin或是Akt的抑制劑－1L-6-hydroxymethyl-chiro-inositol-2- (R)-2-O-methyl-3-O-octade-cylcarbonate（HIMO）而受到抑制。但是IL-1及TNF的產量、NF-kB的活化卻不受加入5-lipoxygenase (5-LOX) 的抑制劑－5,8,11,14-eicosatetraynoic acid （ETYA）或5-LOX activating protein （FLAP）的抑制劑－MK886而受到影響。此外以西方點墨法檢測PBMC在SPEA刺激之後，IκBα、IKKα/β與Akt的磷酸化，以及NF-kB從細胞質移入細胞核的表現量，會因wortmannin或HIMO的加入而受到抑制，卻不受到ETYA或是MK886的影響。另以SPEA處理PBMC後的上清液靜脈注射至兔子體內，會造成兔子體溫明顯增加的情形，會因為加入wortmannin或HIMO而受到抑制，卻不受ETYA或MK886的影響。綜觀以上實驗結果推測，SPEA刺激PBMC會活化NF-kB，誘導致熱性細胞素的產生，可能是透過PI3K-Akt的途徑。

Streptococcal pyrogenic exotoxin A (SPEA) is produced by invasive Streptococcus pyogenes isolated from streptococcal toxic-shock syndrome (STSS) with the severe and frequently fatal illness. The present study provides the first evidence that SPEA acts through the PI3K-Akt and nuclear factor-kappa B (NF-kB)-related mechanism in human peripheral blood mononuclear cells (PBMC) to stimulate the production of pyrogenic cytokines which induced a febrile response in rabbits. The levels of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in the supernatant fluids of SPEA-treated PBMC started to rise at 12 h, reached its plateau levels at 72 h, and displayed dose-dependent manner. Western blot analysis and electrophoretic mobility shift assay (EMSA) demonstrated that SPEA induced the translocation of RelA/p65 into its nucleus and DNA binding activity of NF-kB were also in a dose- and time-dependent manner. The increased levels of TNF and IL-1 in the supernatant fluids and NF-kB nuclear translocation of SPEA-treated PBMC were attenuated by PI3K inhibitor, wortmannin, or Akt inhibitor, 1L-6-hydroxymethyl- chiro-inositol-2-(R)-2-O-methyl-3-O-octadecylcarbonate (HIMO). However, they did not affected by 5-lipoxygenase (5-LOX) inhibitor, 5,8,11,14-eicosatetraynoic acid (ETYA), or 5-LOX activating protein (FLAP) inhibitor, MK886. Moreover, Western blot analysis demonstrated that wortmannin and HIMO, but not ETYA and MK886, inhibited SPEA-mediated phosphorylation of Akt, IKKα/β, and IκBα, and nuclear translocation of NF-kB in PBMC. Furthermore, intravenous administration of supernatant fluids obtained from SPEA-treated PBMC caused the fever in rabbits, and were also attenuated by wortmannin and HIMO, but not ETYA and MK886. Taken together, it appears that the activation of NF-kB increases the production of the pyrogenic cytokines in SPEA-treated PBMC may act through PI3K-Akt pathway.

李一平 (民88) 鏈球菌致熱性外毒素A引起兔子之致熱作用及其作用位置。國立成功大學微生物及免疫學研究所碩士論文，頁1-68。中華民國，台南。
林欣怡 (民88) 鏈球菌致熱性外毒素A刺激週邊單核細胞產生細胞素引起發燒反應。國立成功大學微生物及免疫學研究所碩士論文，頁1-62。中華民國，台南。
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