Oncostatin M Signaling

Cytokines are the principal intercellular mediators of the tissue reaction to trauma and infection. Members of Interleukin 6 (IL-6) hematopoietic cytokine family include IL-6, IL-11, Leukemia Inhibitor Factor (LIF), Oncostatin M (OSM), Ciliary Neurotrophic Factor (CNF), Cardiotrophin-1, and Neurotrophin-1, and play a particularly prominent role in orchestrating initiation and progression of inflammation, hematopoiesis, acute phase response, bone and heart development as well as Neurogenesis. Their redundant effect is attributed to the shared use of the common signal transducing receptor chain GP130. GP130 is homodimerized by IL-6 and IL-11 upon binding to their ligand-specific α-receptors. The other cytokines of this family trigger the heterodimerization of GP130 with the LIFR or the OSMR. Human OSM has the capability to signal both via GP130-LIFR and GP130-OSMR heterodimers to form the high affinity, signaling-competent OSMRI or OSMRII.OSM is produced by activated monocytes and lymphocytes and acts locally on stromal cells. Stromal cells in turn respond prominently by enhanced production of IL-6 and LIF. IL-6 and LIF enter into circulation and participate in the recruitment of systemic inflammatory response that includes the acute phase reaction of the liver. In bovine and human endothelial cells, OSM promotes the expression of urokinase plasminogen activator, basic FGF, GCSF, and GMCSF. In human fibroblasts, OSM modulates not only matrix metalloproteinases but also TIMP. OSM binds to a receptor shared with LIFR-β and GP130, and to a high affinity OSMR-β that binds only OSM and also involves the subunit GP130. The two receptors for OSM may be functionally different and they can be coupled to different signal transduction pathways. Ligand-induced oligomerization of receptor subunits activates JAKs, which in turn phosphorylate tyrosine residues in the receptor cytoplasmic domain. This phosphorylated tyrosine create docking sites for STAT1, STAT3, and STAT5, protein-tyrosine phosphatase SHP2, and linker proteins such as GAB1, GRB2, SOS, or SHC, which propagate the signal to other pathways such as MEK (MAPK/ERK Kinases), ERK1/2 (Extracellular Signal Regulated Kinase), JNK and PI3K. Receptor signaling is manifested by the activation of genes such as acute phase proteins or CDK inhibitor p21/WAF1, which is primarily activated through STATs and immediate early response genes such as c-Fos and c-Jun, primarily through ERK1/2. OSMR-β does not possess a phosphorylation site for ERK1/2 and, thus, do not appear to be appreciably influenced by activated ERK.As a pleiotrophic cytokine, OSM is involved in regulation of the acute phase reaction, hematopoiesis, bone remodeling, and homeostasis of the extracellular matrix, and can act as a mediator for both the proliferation and the growth arrest of various cell lines. OSM inhibits the growth of many cancer cell types, including human melanoma, neuroblastoma, and fibrosarcoma. Due to its ability to induce TIMP1 and TIMP3, profibrotic properties have been attributed to this cytokine. Compared with other IL-6-type cytokines, OSM often induces stronger effects with regard to STAT and MAPK activation, induction of protease inhibitors or growth inhibition. In rheumatoid arthritis, OSM levels correlate with disease severity.