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 , , .
Activated JAK1 phosphorylates
STAT3, which dimerizes and is translocated to the nucleus to
activate transcription of genes containing STAT3 response
elements , , .
Up-regulation of Suppressor of cytokine signaling 3
(SOCS3) gene transcription by STAT3
leads to the termination of IL-6 cytokine
signaling , , , .
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 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
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 , .
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