c-Jun, JAK1, ADAM10, CREB1, IL-6 receptor, C/EBPbeta, c-Raf-1, MEK2, c-Jun, ERK1/2, IL-6, NF-KB, GCR-alpha, SHP-2, Elk-1, SOCS3, STAT3, c-Fos, IL6RA, Gp130, SOS, GRB2, junD, MEK1, C/EBPdelta, ADAM17, H-Ras, C/EBPbeta, Shc, SRF, c-Fos, PtdIns(3,4,5)P3
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 .
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 .
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 , , .
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 , , , , .
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 , , , , , . 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 , , , , , .
c-Jun and c-Fos also cooperate with STAT3 in IL-6 -induced transactivation of target gene promoters containing IL-6 response element (IRE) , . In turn, STAT3 can induce c-Fos gene expression in response to IL-6 .
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 , .
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 , , , , , , , , , , , .
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 , .