IL-6 signaling pathway

IL-6 is a pleiotropic cytokine with important role in immune regulation, hematopoiesis, inflammation and oncogenesis. IL-6-type cytokines exert their action via the signal transducer gp130 that associates with IL6R in a cooperative manner to form a hexameric signal transducing complex, capable of activating the down stream mediators of this signaling pathway. This mechanism of signal transduction is shared by other members of the IL-6 type cytokines like IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1 that use gp130 as a common subunit of the signal transducing complex. IL-6 stimulation leads to the activation of JAK/STAT pathway. Both STAT1 and STAT3 are phosphorylated and are able to form homo- and heterodimers after activation leading to their nuclear localization and subsequent regulation of transcription of respective target genes. SHP-2 is one of the ubiquitous tyrosine phosphatases and IL-6 stimulation leads to the SHP2-dependent activation of MAPKs, it also links the Grb2-SOS complex and Gab1 to gp130. Phosphorylated Gab1 acts as an adapter and is involved in the indirect association of SHP-2 and PI-3 kinase. Downstream activation of Vav1, Rac-1 and MAP2K4 is necessary for the IL-6-mediated STAT3 phosphorylation and transactivation to accomplish its effects. STAT3 is also phosphorylated by PKCD and it causes inhibition of STAT3 DNA binding and transcriptional activity. PTPN11 and SOCS3 exert inhibitory function and thus lead to down regulation of the signaling cascade.

IL-6，一种多效性细胞因子，在免疫调节、造血、炎症和肿瘤发生中扮演着至关重要的角色。IL-6型细胞因子通过信号转导蛋白gp130发挥作用，该蛋白与IL6R以协同方式结合，形成六聚信号转导复合物，能够激活该信号通路下游的介质。这种信号转导机制与其他IL-6型细胞因子成员如IL-11、白血病抑制因子、癌胚素M、睫状神经生长因子和心肌生长因子-1相同，它们均以gp130作为信号转导复合物的共同亚基。IL-6的刺激导致JAK/STAT通路的激活。STAT1和STAT3在激活后均发生磷酸化，并能够形成同源和异源二聚体，导致其核定位，并随后调节相应靶基因的转录。SHP-2是一种普遍存在的酪氨酸磷酸酶，IL-6的刺激导致SHP2依赖性的MAPKs激活，它还连接了Grb2-SOS复合物和Gab1至gp130。磷酸化的Gab1作为适配体，参与SHP-2与PI-3激酶的间接关联。Vav1、Rac-1和MAP2K4的下游激活对于IL-6介导的STAT3磷酸化和转激活是必要的，以实现其效应。STAT3还由PKCD磷酸化，这导致STAT3与DNA结合和转录活性的抑制。PTPN11和SOCS3发挥抑制功能，从而引起信号级联的下调。