白细胞介素 -6 信号
中文名称
通路描述
白细胞介素 -6（IL-6）是一种多效性细胞因子，在免疫调节、造血、炎症、肿瘤发生、代谢控制和睡眠过程中发挥作用。它是 IL-6 相关细胞因子家族（包括 IL-11、IL-27 白血病抑制因子（LIF）、髓神经生长因子（CNTF）和 oncostatin M）的奠基成员。IL-6 受体（IL6R）由一个特异性结合 IL-6 的α亚基和一个β亚基（IL6RB 或 gp130）组成，后者是所有与 IL-6 相关的细胞因子受体的信号传导组分。IL6Rα以膜形式和可溶性形式存在。膜形式主要表达于肝细胞、中性粒细胞、单核细胞/巨噬细胞和一些淋巴细胞。可溶性 IL6R（sIL6R）也由这些细胞表达。sIL6R 的产生有两种主要机制：替代剪接产生缺乏膜结构域的转录本，使用位于膜结构域编码区两侧的剪接供体和剪接受体位点，这也引入了移码，导致在 sIL6R 的 C 末端引入 10 个额外的氨基酸。另一种产生 sIL6R 的机制是膜结合 IL-6R 的蛋白酶解或“脱落”。ADAM10 和 ADAM17 被认为参与此过程（Briso et al. 2008）。sIL6R 可与 IL-6 结合并刺激表达 gp130 但不表达 IL6Rα的细胞，该过程称为跨信号传导。这解释了为什么许多细胞（包括造血祖细胞、神经元细胞、内皮细胞、平滑肌细胞和胚胎干细胞）单独对 IL-6 反应不明显，但对 IL-6/sIL6R 反应显著。跨信号传导通路负责 IL-6 的促炎活性，而膜结合受体则调节再生和抗炎 IL-6 活性。IL6R 信号传导通过两条途径介导：JAK-STAT（Janus 家族酪氨酸激酶 -信号转导和转录激活因子）途径和 Ras-MAPK（细胞外信号调节激酶）途径。IL-6 信号传导的负调节因子包括 SOCS（细胞因子信号抑制因子）和 SHP2。最近开发了许多抗体以抑制 IL-6 活性，其中一些已引入临床用于治疗炎症疾病（Kopf et al. 2010）。
英文描述
Interleukin-6 signaling Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M.
The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities
IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010).
The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities
IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010).
所含基因
11 个基因