Suzuki Nobutaka, Chen Nien-Jung, Millar Douglas G, Suzuki Shinobu, Horacek Thomas, Hara Hiromitsu, Bouchard Denis, Nakanishi Kenji, Penninger Josef M, Ohashi Pamela S, Yeh Wen-Chen
Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
J Immunol. 2003 Apr 15;170(8):4031-5. doi: 10.4049/jimmunol.170.8.4031.
IL-18 is an important cytokine for both innate and adaptive immunity. NK T cells and Th1 cells depend on IL-18 for their divergent functions. The IL-18R, IL-1R, and mammalian Toll-like receptors (TLRs) share homologous intracellular domains known as the TLR/IL-1R/plant R domain. Previously, we reported that IL-1R-associated kinase (IRAK)-4 plays a critical role in IL-1R and TLR signaling cascades and is essential for the innate immune response. Because TLR/IL-1R/plant R-containing receptors mediate signal transduction in a similar fashion, we investigated the role of IRAK-4 in IL-18R signaling. In this study, we show that IL-18-induced responses such as NK cell activity, Th1 IFN-gamma production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice. IRAK-4(-/-) Th1 cells also do not exhibit NF-kappaB activation or IkappaB degradation in response to IL-18. Moreover, AP-1 activation which is triggered by c-Jun N-terminal kinase activation is also completely inhibited in IRAK-4(-/-) Th1 cells. These results suggest that IRAK-4 is an essential component of the IL-18 signaling cascade.
白细胞介素-18(IL-18)是先天性免疫和适应性免疫中的一种重要细胞因子。自然杀伤T细胞(NK T细胞)和辅助性T1细胞(Th1细胞)的不同功能依赖于IL-18。IL-18受体(IL-18R)、IL-1受体(IL-1R)和哺乳动物Toll样受体(TLR)共享被称为TLR/IL-1R/植物R结构域的同源细胞内结构域。此前,我们报道IL-1R相关激酶(IRAK)-4在IL-1R和TLR信号级联反应中起关键作用,并且对先天性免疫反应至关重要。由于含TLR/IL-1R/植物R的受体以相似方式介导信号转导,我们研究了IRAK-4在IL-18R信号传导中的作用。在本研究中,我们发现,在缺乏IRAK-4的小鼠中,IL-18诱导的反应,如NK细胞活性、Th1干扰素-γ产生和Th1细胞增殖均严重受损。IRAK-4基因敲除(IRAK-4(-/-))小鼠中的Th1细胞对IL-18也不表现出核因子-κB(NF-κB)激活或IκB降解。此外,由c-Jun氨基末端激酶激活触发的激活蛋白-1(AP-1)激活在IRAK-4(-/-) Th1细胞中也完全受到抑制。这些结果表明,IRAK-4是IL-18信号级联反应的一个重要组成部分。