白细胞介素 -18 信号传导
中文名称
通路描述
白细胞介素 -18 信号传导。白细胞介素 -18（IL18，前体 IL18）是一种多效性和促炎细胞因子。它属于白细胞介素 -1（IL1 超家族）。IL18 以 24 kDa 的无活性前体蛋白形式合成，由细胞外蛋白酶如 caspase-1、蛋白酶 3、丝氨酸蛋白酶、弹性蛋白酶或 cathepsin G 等切割，形成 18 kDa 的成熟蛋白。IL18 还以短异构体形式存在，这是通过替代剪接事件去除 57 bp/19 个氨基酸（IL18alpha）的结果。该短异构体与 IL18 经典活性形式具有适度的协同作用。IL18 受体（IL18R）属于白细胞介素 -1 受体/ Toll 样受体超家族。它由两个亚基组成：白细胞介素 -18 受体 1（IL18R1，IL-18Rα，IL1Rrp1，IL18R1，IL-1R5）和白细胞介素 -18 受体辅助蛋白（IL18RAP，IL18RB，IL-18Rβ，IL-18RacP，IL-18RII 或 IL-1R7）。两个亚基都具有三个细胞外免疫球蛋白样结构域和一个细胞内 Toll/IL-1 受体（TIR）结构域（O'Neill 和 Dinarello 2000，Sims 2002）。据认为，IL18 首先结合 IL18R1，然后招募 IL18RAP 形成高亲和力的异三聚体复合物（Sims 2002，Sergi 和 Pentilla 2004，Alboni 等人，2009）。IL18R1 的短异构体缺乏 TIR 结构域（IL18R1 类型 II），这是信号传导所必需的，导致建议 IL18R1 类型 II 是假受体（Colotta 等人，1994）。IL18RAP 的截短形式仅包含三个免疫球蛋白结构域中的一个，稳定 IL18 与 IL18R1 的结合但阻止信号传导。IL18 结合蛋白（IL18BP）是一种 38 kDa 的可溶性蛋白，是 IL18 信号传导的另一个负调节因子。它与 IL18R1 具有序列同源性（Im 等人，2002，Kim 等人，2002，Novick 等人，1999）。IL18BP 与成熟 IL18 具有高亲和力结合，阻止其与 IL18R1 的结合。已描述多种 IL18BP 异构体（Kim 等人，2000）。白细胞介素 -37（IL37，IL-1F7），另一个 IL18 信号传导的负调节因子，能够结合 IL18BP 和 IL18RAP 阻止信号传导（Bufler 等人，2002，Pan 等人，2001，Kumar 等人，2002）。IL18 刺激 T 辅助淋巴细胞细胞（Th1）和巨噬细胞产生干扰素 -γ（IFNG，IFN-γ），并增强自然杀伤（NK）细胞的细胞毒性。IL18 刺激的 IFNG 产生由其他 Th1 相关细胞因子如 IL2、IL15、IL12 和 IL23 协同放大（Boraschi 和 Dinarello 2006，Park 等人，2007，Dinarello 2007，Dinarello 和 Fantuzzi 2003）。
英文描述
Interleukin-18 signaling Interleukin-18 (IL18, pro-IL18) is a pleiotropic and pro inflammatory cytokine. It belongs to the Interleukin-1 (IL1 superfamily (Alboni et al. 2010, Krumm et al. 2017, Dinarello 1999). IL18 is synthesized as an inactive 24-kDa precursor protein that is cleaved by extracellular proteases such as caspase-1, protease 3, serine protease, elastase or cathepsin G (Fantuzzi & Dinarello 1999, Gracie et al. 2004, Sugawara et al. 2001), forming an 18-kDa mature protein (Arend et al. 2008, Akita et al. 1997, Fantuzzi et al. 1998, Ghayur et al. 1997, Gu et al. 1997, Ushio et al. 1996).
IL18 also occurs as a short isoform, the result of an alternative splicing event that removes 57 bp/19 aa (IL18alpha) (Conti et al. 1997, Yang et al. 2005). This short isoform has a modest synergistic action with the IL18 canonical active form. The IL18 receptor (IL18R) belongs to the Interleukin-1 receptor/Toll like receptor superfamily. It consists of two subunits, Interleukin-18 receptor 1 (IL18R1, IL-18Rα, IL1Rrp1, IL18R1, IL-1R5) and Interleukin-18 receptor accessory protein (IL18RAP, IL18RB, IL-18Rβ,IL-18RacP, IL-18RII or IL-1R7). Both subunits have three extracellular immunoglobulin-like domains and one intracellular Toll/IL-1 receptor (TIR) domain (O'Neill & Dinarello 2000, Sims 2002). It is believed that IL18 binds first to IL18R1 and later recruits IL18RAP to form a high-affinity heterotrimeric complex (Sims 2002, Sergi & Pentilla 2004, Alboni et al. 2009). A short isoform of IL18R1 lacks the TIR domain (IL18R1 type II) (Alboni et al. 2009), which is required for signaling, leading to the suggestion that IL18R1 type II is a decoy receptor (Colotta et al. 1994). A truncated form of IL18RAP containing only one of the three immunoglobulin domains stabilizes IL18 binding to IL18R1 but prevents signaling.
IL-18 binding protein (IL18BP), a 38-kDa soluble protein, is another negative regulator of IL18 signaling. It has some sequence homology with IL18R1 (Im et al. 2002 , Kim et al. 2002, Novick et al. 1999). IL18BP binds with high affinity to mature IL18, preventing its interaction with IL18R1. Several isoforms IL18BP have been described (Kim et al. 2000). Interleukin-37 (IL37, IL-1F7), another negative regulator of IL18 signaling, is able to bind IL18BP and IL18RAP preventing signaling (Bufler et al.2002, Pan et al. 2001, Kumar et al. 2002).
IL18 stimulates Interferon gamma (IFNG, IFN-γ) production from T-helper lymphocytes cells (Th1) and macrophages and enhances the cytotoxicity of natural killer (NK) cells. IL18 stimulated IFNG production is synergistically amplified by other Th1-related cytokines such as IL2, IL15, IL12 and IL23 (Boraschi & Dinarello 2006, Park et al. 2007, Dinarello 2007, Dinarello & Fantuzzi 2003).
IL18 also occurs as a short isoform, the result of an alternative splicing event that removes 57 bp/19 aa (IL18alpha) (Conti et al. 1997, Yang et al. 2005). This short isoform has a modest synergistic action with the IL18 canonical active form. The IL18 receptor (IL18R) belongs to the Interleukin-1 receptor/Toll like receptor superfamily. It consists of two subunits, Interleukin-18 receptor 1 (IL18R1, IL-18Rα, IL1Rrp1, IL18R1, IL-1R5) and Interleukin-18 receptor accessory protein (IL18RAP, IL18RB, IL-18Rβ,IL-18RacP, IL-18RII or IL-1R7). Both subunits have three extracellular immunoglobulin-like domains and one intracellular Toll/IL-1 receptor (TIR) domain (O'Neill & Dinarello 2000, Sims 2002). It is believed that IL18 binds first to IL18R1 and later recruits IL18RAP to form a high-affinity heterotrimeric complex (Sims 2002, Sergi & Pentilla 2004, Alboni et al. 2009). A short isoform of IL18R1 lacks the TIR domain (IL18R1 type II) (Alboni et al. 2009), which is required for signaling, leading to the suggestion that IL18R1 type II is a decoy receptor (Colotta et al. 1994). A truncated form of IL18RAP containing only one of the three immunoglobulin domains stabilizes IL18 binding to IL18R1 but prevents signaling.
IL-18 binding protein (IL18BP), a 38-kDa soluble protein, is another negative regulator of IL18 signaling. It has some sequence homology with IL18R1 (Im et al. 2002 , Kim et al. 2002, Novick et al. 1999). IL18BP binds with high affinity to mature IL18, preventing its interaction with IL18R1. Several isoforms IL18BP have been described (Kim et al. 2000). Interleukin-37 (IL37, IL-1F7), another negative regulator of IL18 signaling, is able to bind IL18BP and IL18RAP preventing signaling (Bufler et al.2002, Pan et al. 2001, Kumar et al. 2002).
IL18 stimulates Interferon gamma (IFNG, IFN-γ) production from T-helper lymphocytes cells (Th1) and macrophages and enhances the cytotoxicity of natural killer (NK) cells. IL18 stimulated IFNG production is synergistically amplified by other Th1-related cytokines such as IL2, IL15, IL12 and IL23 (Boraschi & Dinarello 2006, Park et al. 2007, Dinarello 2007, Dinarello & Fantuzzi 2003).
所含基因
8 个基因