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 of hematopoietic and neurotrophic cytokines known as the Interleukin 6 (IL6)-type cytokine family [1].

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 [2].

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 [3], [4], [5]. 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 [2].

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

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 [1].

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 [7]. 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 [8].

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 [9]. 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 STAT3-dependent [10].

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) [2], [11].

Oncostatin M participates in induction of epithelial-to-mesenchymal transition (EMT) of renal cells via JAK/STAT1 and STAT2. STAT activation leads to E-cadherin downregulation and alpha-smooth muscle actin upregulation [12]. 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 [13], [14], [15]. [12], [16].

References:

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   Activation of the JAK-STAT signal transduction pathway by oncostatin-M cultured human and mouse osteoblastic cells. Endocrinology 1996 Apr;137(4):1159-65
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