Immune response IL-6 signaling pathway
IL-6 signaling pathway
Interleukin-6 ( IL-6 ) is a pleiotropic cytokine produced by various types oflymphoid and nonlymphoid cells, such as T cells, B cells, monocytes, fibroblasts,keratinocytes, endothelial cells, mesangial cells and several tumor cells. IL-6provokes a broad range of cellular and physiological responses, including the immuneresponse, inflammation, hematopoiesis and oncogenesis by regulating cell growth, geneactivation, proliferation, survival and differentiation [1].
IL-6 signals through IL-6 receptor composed of two differentsubunits, Interleukin 6 receptor alpha subunit ( IL6RA ) that produces ligandspecificity and Interleukin 6 signal transducer ( gp130 ), a receptor subunitshared with other cytokines of the IL-6 family [2].
Binding of IL-6 to its receptor initiates cellular events including activationof 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 istranslocated to the nucleus to activate transcription of genes containing STAT3response elements [6], [7], [3].
Up-regulation of Suppressor of cytokine signaling 3 ( SOCS3 ) genetranscription 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 tyrosinephosphatase non-receptor type 11 ( SHP-2 ) that associates with SHC transformingprotein 1 ( Shc ) and Growth factor receptor-bound protein 2 ( GRB2 )followed by activation of the ERK1/2 signaling [12], [13],[14], [15], [4].
Shc/ GRB2/ Son of sevenless homologs ( SOS )/ v-Ha-ras Harveyrat sarcoma viral oncogene homolog ( H-Ras )/ v-Raf-1 murine leukemia viraloncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2 )/ ERK1/2 pathway activates transcription factors suchas ELK1 member of ETS oncogene family ( Elk-1 ) and CCAAT/enhancer binding proteinbeta ( C/EBPbeta ) that act through their own cognate response elements in thegenome [16], [17], [1], [18], [19], [20]. These factors and other transcription factors, includingv-Fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ), Jun oncogene (c-Jun ) and Serum response factor ( SRF ) regulate a variety of complexpromoters and enhancers that respond to IL-6 [21], [22],[23], [24], [25], [5].
c-Jun and c-Fos also cooperate with STAT3 in IL-6 -inducedtransactivation of target gene promoters containing IL-6 response element (IRE) [26], [27]. In turn, STAT3 can induce c-Fos geneexpression in response to IL-6 [18].
IL-6 activates cells by binding to the membrane-bound IL6RA andsubsequent formation of a complex with gp130 homodimer. Cells that expressgp130, but not IL6RA, can be activated by IL-6 and the solubleIL6RA which is produced by shedding from the cell surface by metalloproteinasesADAM17 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 oftranscription factors, including Nuclear factor-kappa B ( NF-kB ),C/EBPbeta, CCAAT/enhancer binding protein delta ( C/EBPdelta ), cAMPresponsive 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 aregulatory link between the endocrine and immune systems. Ligand-activated Glucocorticoidreceptor ( GCR-alpha ) represses the IL-6 gene transcription by occlusionnot only of the inducible IL-6 enhancer region but also of the basal IL-6promoter elements [42], [43].
Map Key
