Immune response - IL-6 signaling pathway

IL-6 signaling pathway

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by various types of lymphoid and nonlymphoid cells, such as T cells, B cells, monocytes, fibroblasts, keratinocytes, endothelial cells, mesangial cells and several tumor cells. IL-6 provokes a broad range of cellular and physiological responses, including the immune response, inflammation, hematopoiesis and oncogenesis by regulating cell growth, gene activation, proliferation, survival and differentiation [1].

IL-6 signals through IL-6 receptor composed of two different subunits, Interleukin 6 receptor alpha subunit (IL6RA) that produces ligand specificity and Interleukin 6 signal transducer (gp130), a receptor subunit shared with other cytokines of the IL-6 family [2].

Binding of IL-6 to its receptor initiates cellular events including activation of Janus kinase 1 (JAK1)/ Signal transducer and activator of transcription 3 (STAT3) and Extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling pathways [3], [4], [5].

Activated JAK1 phosphorylates STAT3, which dimerizes and is translocated to the nucleus to activate transcription of genes containing STAT3 response elements [3], [6], [7].

Up-regulation of Suppressor of cytokine signaling 3 (SOCS3) gene transcription by STAT3 leads to the termination of IL-6 cytokine signaling [8], [9], [10], [11].

JAK1 is also required for the tyrosine phosphorylation of Protein tyrosine phosphatase non-receptor type 11 (SHP-2) that associates with SHC transforming protein 1 (Shc) and Growth factor receptor-bound protein 2 (GRB2) followed by activation of the ERK1/2 signaling [4], [12], [13], [14], [15].

Shc/ GRB2/ Son of sevenless homologs (SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ ERK1/2 pathway activates transcription factors such as ELK1 member of ETS oncogene family (Elk-1) and CCAAT/enhancer binding protein beta (C/EBPbeta) that act through their own cognate response elements in the genome [1], [16], [17], [18], [19], [20]. These factors and other transcription factors, including v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos), Jun oncogene (c-Jun) and Serum response factor (SRF) regulate a variety of complex promoters and enhancers that respond to IL-6 [5], [21], [22], [23], [24], [25].

c-Jun and c-Fos also cooperate with STAT3 in IL-6-induced transactivation of target gene promoters containing IL-6 response element (IRE) [26], [27]. In turn, STAT3 can induce c-Fos gene expression in response to IL-6 [18].

IL-6 activates cells by binding to the membrane-bound IL6RA and subsequent formation of a complex with gp130 homodimer. Cells that express gp130, but not IL6RA, can be activated by IL-6 and the soluble IL6RA which is produced by shedding from the cell surface by metalloproteinases ADAM17 and ADAM10 [28], [29].

In response to a variety of signals, such as bacterial pathogens, Interleukin-1 beta (IL-1 beta), Tumor necrosis factor alpha (TNF-alpha), Transforming growth factor, beta 1 (TGF-beta 1) etc., IL-6 gene expression is up-regulated by a wide range of transcription factors, including Nuclear factor-kappa B (NF-kB), C/EBPbeta, CCAAT/enhancer binding protein delta (C/EBPdelta), cAMP responsive element binding protein 1 (CREB1), Jun D proto-oncogene (junD), v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos), Jun oncogene (c-Jun), depending on cell type and ligand specificity [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41].

The feedback inhibition of IL-6 gene expression by glucocorticoids represents a regulatory link between the endocrine and immune systems. Ligand-activated Glucocorticoid receptor (GCR-alpha) represses the IL-6 gene transcription by occlusion not only of the inducible IL-6 enhancer region but also of the basal IL-6 promoter elements [42], [43].

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