Oncostatin M signaling via JAK-Stat in human
Oncostatin M is a multifunctional cytokine produced by
activated T lymphocytes, monocytes, microglia. It is structurally and functionally
related to the subfamily of hematopoietic and neurotrophic cytokines known as the
Interleukin 6 (IL6)-type cytokine family .
Human Oncostatin M and mouse Oncostatin M
signaling pathways are different. Human Oncostatin
M signaling is mediated by its binding to two receptor complexes: the type
I OSM receptor complex (LIF receptor) consisting of
Interleukin 6 signal transducer (gp130) and Leukemia
inhibitory factor receptor subunits (LIFR), and the type II
OSM receptor complex (OSM receptor) consisting of
gp130 and OSM receptor beta
(OSMR) subunits. Mouse Oncostatin
M uses only one receptor complex: OSM
receptor, but not LIF receptor .
Binding of Oncostatin M to its receptor subunits induces
the Janus kinases (JAK)/ signal transducer and activator of transcription (STAT)
signaling pathway. Janus kinase 1 (Jak1), Janus kinase 2
(Jak2) and Tyrosine kinase 2
(Tyk2) may associate with OSM
receptor and LIF receptor , , . Signaling capacity of
LIFR or OSMR depends on the
cellular context. Activated JAKs recruit and activate STAT proteins. Phosphorylated STATs
then dimerize, translocate to the nucleus, bind to regulatory elements in the promoter of
OSM-responsive genes and induce gene expression. Oncostatin
M predominantly activates Signal transducers and activators of
transcription 1, 3 and 5
(STAT1, STAT3 and
STAT5) in a variety of cell types .
Suppressor of cytokine signaling 3 (SOCS-3) is an
inhibitor of Oncostatin M signals.
SOCS-3 transcription may be stimulated by
Oncostatin M .
Oncostatin M is involved in a variety of biological
activities such as inflammation, remodeling of extracellular matrix and modulation of
cell growth and differentiation and other .
Oncostatin M may regulate cell growth, e.g., via Vascular
endothelial growth factor A (VEGF-A) or Cyclin
D1. Oncostatin M induces
VEGF promoter activity in an OSM
receptor/ STAT-3-dependent manner . Oncostatin M
regulates Cyclin D1 expression via
STAT3 in a cell specific-dependent manner. It is shown, that
Oncostatin M inhibits expression of Cyclin
D1 in fetal hepatocytes but up-regulates in hepatic tumor cells .
Oncostatin M regulates inflammation both directly and
indirectly via the production of other cytokines and their receptors. For example,
Oncostatin M may activate transcription of inflammatory
reactant Serpin peptidase inhibitor clade A member 3 (SERPINA3
(ACT)) via STAT1 and/or STAT3
. In addition, Oncostatin M
induces transcription of eosinophil-specific C-C chemokine that is implicated in the
pathogenesis of eosinophilic inflammatory diseases - Chemokine ligand 11
(Eotaxin). This process is
Remodeling of the extracellular matrix is important for healing the damaged tissue
induced by inflammatory responses. Oncostatin M stimulation
of the JAK/ STAT signaling pathway in primary chondrocytes
leads to induction of important element regulation of this process - e.g., Matrix
metallopeptidase 1 (MMP1) and TIMP metallopeptidase
inhibitor 1 (TIMP-1) , .
Oncostatin M participates in induction of
epithelial-to-mesenchymal transition (EMT) of renal cells via
STAT2. STAT activation leads to
E-cadherin downregulation and alpha-smooth muscle actin
upregulation . Normally, EMT seems to be a process, induced during wound
healing after injury. And EMT can be a normal recovery process in renal cells, because
proliferating myofibroblasts are produced during it. EMT of renal cells can lead to renal
fibrosis progression , , . , .
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STAT3 down-regulates the expression of cyclin D during liver development.
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