Dinarello C A
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver 80262, USA.
J Allergy Clin Immunol. 1999 Jan;103(1 Pt 1):11-24. doi: 10.1016/s0091-6749(99)70518-x.
Formerly called IFN-gamma-inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as TH1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-lR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18Rbeta, also a member of the IL-1R family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.
白细胞介素-18曾被称为γ干扰素诱导因子，是一种新型细胞因子的新名称，它在TH1应答中发挥重要作用，主要是通过其诱导T细胞和自然杀伤细胞产生γ干扰素的能力。尽管存在白细胞介素-12，但缺乏白细胞介素-18的小鼠其γ干扰素的产生受到抑制。白细胞介素-18在结构和功能方面均与白细胞介素-1家族相关。在结构上，白细胞介素-18和白细胞介素-1β具有显著的一级氨基酸序列，并且作为全β折叠片层分子具有相似的折叠方式。与白细胞介素-1β相似，白细胞介素-18也作为一种缺乏信号肽的无生物学活性的前体分子被合成。研究表明，与白细胞介素-1β前体相似，白细胞介素-18前体需要被细胞内的半胱氨酸蛋白酶白细胞介素-1β转换酶（ICE，也称为半胱天冬酶-1）切割成有活性的成熟分子。因此，ICE活性抑制剂可能会限制白细胞介素-18的生物学活性，并且可能作为TH1免疫抑制剂发挥作用。成熟白细胞介素-18的活性与白细胞介素-1的活性密切相关。白细胞介素-18可诱导肿瘤坏死因子、白细胞介素-1、Fas配体和几种趋化因子的基因表达和合成。白细胞介素-18的活性是通过一种假定的白细胞介素-18受体（IL-18R）复合物的信号传导链来实现的。这种IL-18R复合物由一条称为IL-18Rα的结合链、白细胞介素-1受体家族的一个成员（以前被鉴定为白细胞介素-1受体相关蛋白（IL-1Rrp））以及一条信号传导链IL-18Rβ组成，IL-18Rβ也是白细胞介素-1受体家族的一个成员。IL-18R复合物募集白细胞介素-1受体激活激酶和肿瘤坏死因子受体相关因子-6，后者使核因子κB（NFκB）诱导激酶磷酸化，随后激活NFκB。因此，基于白细胞介素-18的一级结构、三维结构、受体家族、信号转导途径和生物学效应，似乎可将这种细胞因子归为白细胞介素-1家族。与白细胞介素-1相似，白细胞介素-18参与先天性免疫和获得性免疫。
