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Immune response Oncostatin M signaling via JAK-Stat in human cells


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Immune response Oncostatin M signaling via JAK-Stat in human cells

Oncostatin M signaling via JAK-Stat in human cells

Oncostatin M is a multifunctional cytokine produced by activated T lymphocytes,monocytes, microglia. It is structurally and functionally related to the subfamily ofhematopoietic and neurotrophic cytokines known as the Interleukin 6 (IL6)-type cytokinefamily [1].

Human Oncostatin M and mouse Oncostatin M signaling pathways aredifferent. Human Oncostatin M signaling is mediated by its binding to two receptorcomplexes: the type I OSM receptor complex ( LIF receptor ) consisting ofInterleukin 6 signal transducer ( gp130 ) and Leukemia inhibitory factor receptorsubunits ( LIFR ), and the type II OSM receptor complex ( OSM receptor )consisting of gp130 and OSM receptor beta ( OSMR ) subunits. MouseOncostatin M uses only one receptor complex: OSM receptor, but not LIFreceptor [2].

Binding of Oncostatin M to its receptor subunits induces the Janus kinases(JAK)/ signal transducer and activator of transcription (STAT) signaling pathway. Januskinase 1 ( Jak1), Janus kinase 2 ( Jak2) and Tyrosine kinase 2 (Tyk2 ) may associate with OSM receptor and LIF receptor [3], [4], [5]. Signaling capacity of LIFR orOSMR depends on the cellular context. Activated JAKs recruit and activate STATproteins. Phosphorylated STATs then dimerize, translocate to the nucleus, bind toregulatory elements in the promoter of OSM-responsive genes and induce gene expression.Oncostatin M predominantly activates Signal transducers and activators oftranscription 1, 3 and 5 ( STAT1, STAT3 and STAT5 ) in a variety ofcell types [2].

Suppressor of cytokine signaling 3 ( SOCS-3 ) is an inhibitor of OncostatinM signals. SOCS-3 transcription may be stimulated by Oncostatin M[6].

Oncostatin M is involved in a variety of biological activities such asinflammation, remodeling of extracellular matrix and modulation of cell growth anddifferentiation and other [1].

Oncostatin M may regulate cell growth, e.g., via Vascular endothelial growthfactor A ( VEGF-A ) or Cyclin D1. Oncostatin M induces VEGFpromoter activity in an OSM receptor/ STAT-3 -dependent manner [7]. Oncostatin M regulates Cyclin D1 expression via STAT3 ina cell specific -dependent manner. It is shown, that Oncostatin M inhibitsexpression of Cyclin D1 in fetal hepatocytes but up-regulates in hepatic tumorcells [8].

Oncostatin M regulates inflammation both directly and indirectly via theproduction of other cytokines and their receptors. For example, Oncostatin M mayactivate transcription of inflammatory reactant Serpin peptidase inhibitor clade A member3 ( SERPINA3 (ACT) ) via STAT1 and/or STAT3 [9]. Inaddition, Oncostatin M induces transcription of eosinophil-specific C-C chemokinethat is implicated in the pathogenesis of eosinophilic inflammatory diseases - Chemokineligand 11 ( Eotaxin ). This process is STAT3 -dependent [10].

Remodeling of the extracellular matrix is important for healing the damaged tissueinduced by inflammatory responses. Oncostatin M stimulation of the JAK/ STATsignaling pathway in primary chondrocytes leads to induction of important elementregulation of this process - e.g., Matrix metallopeptidase 1 ( MMP1 ) and TIMPmetallopeptidase inhibitor 1 ( TIMP-1) [11], [2].