Kinjo Yuki, Kawakami Kazuyoshi, Uezu Kaori, Yara Satomi, Miyagi Kazuya, Koguchi Yoshinobu, Hoshino Tomoaki, Okamoto Masaki, Kawase Yusuke, Yokota Koichi, Yoshino Kohichiro, Takeda Kiyoshi, Akira Shizuo, Saito Atsushi
Faculty of Medicine, First Department of Internal Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
J Immunol. 2002 Jul 1;169(1):323-9. doi: 10.4049/jimmunol.169.1.323.
The present study was conducted to critically determine the protective role of IL-18 in host response to Mycobacterium tuberculosis infection. IL-18-deficient (knockout (KO)) mice were slightly more prone to this infection than wild-type (WT) mice. Sensitivity of IL-12p40KO mice was lower than that of IL-12p40/IL-18 double KO mice. IFN-gamma production caused by the infection was significantly attenuated in IL-18KO mice compared with WT mice, as indicated by reduction in the levels of this cytokine in sera, spleen, lung, and liver, and its synthesis by spleen cells restimulated with purified protein derivatives. Serum IL-12p40 level postinfection and its production by peritoneal exudate cells stimulated with live bacilli were also significantly lower in IL-18KO mice than WT mice, suggesting that attenuated production of IFN-gamma was secondary to reduction of IL-12 synthesis. However, this was not likely the case, because administration of excess IL-12 did not restore the reduced IFN-gamma production in IL-18KO mice. In further studies, IL-18 transgenic mice were more resistant to the infection than control littermate mice, and serum IFN-gamma level and its production by restimulated spleen cells were increased in the former mice. Taken together, our results indicate that IL-18 plays an important role in Th1 response and host defense against M. tuberculosis infection although the contribution was not as profound as that of IL-12p40.
本研究旨在严格确定白细胞介素-18（IL-18）在宿主对结核分枝杆菌感染反应中的保护作用。白细胞介素-18缺陷型（敲除（KO））小鼠比野生型（WT）小鼠更容易感染这种病菌。白细胞介素-12p40敲除小鼠的易感性低于白细胞介素-12p40/白细胞介素-18双敲除小鼠。与野生型小鼠相比，白细胞介素-18敲除小鼠感染后产生的γ干扰素显著减少，血清、脾脏、肺和肝脏中该细胞因子水平降低以及经纯化蛋白衍生物再次刺激的脾细胞合成γ干扰素均表明了这一点。感染后白细胞介素-18敲除小鼠的血清白细胞介素-12p40水平及其经活杆菌刺激的腹腔渗出细胞产生的白细胞介素-12p40也显著低于野生型小鼠，这表明γ干扰素产生减少是白细胞介素-12合成减少的继发结果。然而，情况可能并非如此，因为给予过量白细胞介素-12并不能恢复白细胞介素-18敲除小鼠中减少的γ干扰素产生。在进一步的研究中，白细胞介素-18转基因小鼠比对照同窝小鼠对感染更具抵抗力，并且前者小鼠的血清γ干扰素水平及其经再次刺激的脾细胞产生的γ干扰素增加。综上所述，我们的结果表明，白细胞介素-18在Th1反应和宿主抵抗结核分枝杆菌感染的防御中起重要作用，尽管其作用不如白细胞介素-12p40那样显著。
