Nakamatsu Masashi, Yamamoto Natsuo, Hatta Masumitsu, Nakasone Chikara, Kinjo Takeshi, Miyagi Kazuya, Uezu Kaori, Nakamura Kiwamu, Nakayama Toshinori, Taniguchi Masaru, Iwakura Yoichiro, Kaku Mitsuo, Fujita Jiro, Kawakami Kazuyoshi
Department of Medicine and Therapeutics, Control and Prevention of Infectious Diseases, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Microbes Infect. 2007 Mar;9(3):364-74. doi: 10.1016/j.micinf.2006.12.003. Epub 2007 Jan 9.
Previously, we demonstrated that Valpha14+ NKT cells and IFN-gamma are important upstream components in neutrophil-mediated host defense against infection with Streptococcus pneumoniae. In the present study, we extended these findings by elucidating the role of IFN-gamma in this Valpha14+ NKT cell-promoted process. Administration of recombinant IFN-gamma to Jalpha18KO mice prolonged the shortened survival, promoted the attenuated clearance of bacteria and improved the reduced accumulation of neutrophils and synthesis of MIP-2 and TNF-alpha in the lungs, in comparison to wild-type (WT) mice. In addition, intravenous transfer of liver mononuclear cells (LMNC) from WT mice into Jalpha18KO mice resulted in complete recovery of the depleted responses listed above, whereas such effects were not detected when LMNC were obtained from IFN-gammaKO or Jalpha18KO mice. Activation of Valpha14+ NKT cells by alpha-galactosylceramide (alpha-GalCer) significantly enhanced the clearance of bacteria, accumulation of neutrophils and synthesis of MIP-2 and TNF-alpha in the infected lungs; this effect was significantly inhibited by a neutralizing anti-IFN-gamma antibody. Finally, in a flow cytometric analysis, TNF-alpha synthesis was detected largely by CD11b(bright+) cells in the infected lungs. Our results demonstrated that IFN-gamma plays an important role in the neutrophil-mediated host protective responses against pneumococcal infection promoted by Valpha14+ NKT cells.
此前，我们证明了Vα14 + NKT细胞和IFN-γ是中性粒细胞介导的宿主防御肺炎链球菌感染的重要上游成分。在本研究中，我们通过阐明IFN-γ在这个Vα14 + NKT细胞促进的过程中的作用，扩展了这些发现。与野生型（WT）小鼠相比，给Jα18KO小鼠注射重组IFN-γ可延长缩短的生存期，促进减弱的细菌清除，并改善肺中中性粒细胞积累减少以及MIP-2和TNF-α合成减少的情况。此外，将WT小鼠的肝单核细胞（LMNC）静脉内转移到Jα18KO小鼠中导致上述耗尽反应完全恢复，而当从IFN-γKO或Jα18KO小鼠获得LMNC时未检测到这种效果。用α-半乳糖神经酰胺（α-GalCer）激活Vα14 + NKT细胞可显著增强感染肺中的细菌清除、中性粒细胞积累以及MIP-2和TNF-α合成；这种作用被中和性抗IFN-γ抗体显著抑制。最后，在流式细胞术分析中，感染肺中的TNF-α合成主要由CD11b（亮 +）细胞检测到。我们的结果表明，IFN-γ在Vα14 + NKT细胞促进的中性粒细胞介导的宿主抗肺炎球菌感染的保护性反应中起重要作用。
