Sireci Guido, La Manna Marco Pio, Di Liberto Diana, Lo Dico Marco, Taniguchi Masaru, Dieli Francesco, Salerno Alfredo
Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo, Italy.
J Leukoc Biol. 2008 Aug;84(2):550-60. doi: 10.1189/jlb.0707499. Epub 2008 May 5.
The NKT cell ligand alpha-galactosylceramide and its synthetic homologue KRN7000 stimulate rapid and copious secretion of IFN-gamma and TNF-alpha release, both of which are key mediators of LPS-induced shock. We showed that KRN7000, injected before or within 2 h after LPS challenge, was able to prevent endotoxic shock. KRN7000 induced survival when the mice were injected 6, 9, or 12 days before the first injection of LPS, and this protective effect was associated with reduction upon subsequent challenge in the levels of IFN-gamma, TNF-alpha, MCP-1, and an increase of IL-10. Further analysis showed that the animals treated with KRN7000 prior to LPS challenge had lower numbers of F4/80+, NKT, and NK cells and lower percentages of NKT cells that stained for intracytoplasmic IFN-gamma when compared with mice that were not treated with KRN7000. When MCP-1 was injected in KRN7000-treated mice, the lethal effect of LPS challenge was restored, and the numbers of F4/80+, NKT, and NK cells increased to levels similar to those in untreated mice following LPS challenge. Taken together, our data demonstrated that KRN7000, injected from 6 to 12 days before the first administration of LPS, prevented endotoxin shock by inhibiting IFN-gamma, TNF-alpha, and MCP-1 release.
自然杀伤T细胞（NKT细胞）配体α-半乳糖神经酰胺及其合成类似物KRN7000可刺激大量快速分泌γ干扰素（IFN-γ）并释放肿瘤坏死因子-α（TNF-α），这两者都是脂多糖（LPS）诱导休克的关键介质。我们发现，在LPS攻击前或攻击后2小时内注射KRN7000能够预防内毒素休克。当在首次注射LPS前6、9或12天给小鼠注射KRN7000时可诱导其存活，这种保护作用与后续攻击时IFN-γ、TNF-α、单核细胞趋化蛋白-1（MCP-1）水平降低以及白细胞介素-10（IL-10）增加有关。进一步分析表明，与未用KRN7000处理的小鼠相比，在LPS攻击前用KRN7000处理的动物F4/80⁺、NKT和NK细胞数量较少，且胞质内IFN-γ染色的NKT细胞百分比也较低。当给用KRN7000处理的小鼠注射MCP-1时，LPS攻击的致死效应得以恢复，F4/80⁺、NKT和NK细胞数量增加至与LPS攻击后未处理小鼠相似的水平。综上所述，我们的数据表明，在首次给予LPS前6至12天注射KRN7000可通过抑制IFN-γ、TNF-α和MCP-1释放来预防内毒素休克。
