Enhancement of placenta growth factor expression by oncostatin M in human rheumatoid arthritis synovial fibroblasts

Abstract

Oncostatin M (OSM) belongs to IL-6 subfamily and is mostly produced by T lymphocytes. High levels of OSM are detected in the pannus of rheumatoid arthritis (RA) patients and it may arouse the inflammation responses in joints and eventually leads to bone erosion. Placenta growth factor (PLGF) is an angiogenic factor and highly homologous with vascular endothelial growth factor (VEGF). It has been recently reported that PLGF is highly expressed in synovial tissue and enhances the production of proinflammatory cytokines including TNF-α and IL-6. Here, we demonstrated that OSM increased mRNA and protein levels of PLGF in a time- and concentration-dependent manner in RA synovial fibroblasts. Inhibitors of JAK3 and PI3K antagonized OSM-induced production of PLGF. OSM enhanced the phosphorylation of Tyr705-STAT3, Ser727-STAT3, Ser473-Akt, and increased the nuclear translocation of phosphorylated STAT3 time-dependently. Transfection of dominant negative Akt or application of PI3K inhibitorLY294002 significantly inhibited p-Tyr705-STAT3, p-Ser727-STAT3, and PLGF expression, indicating that Akt is involved in JAK3/STAT3/PLGF signaling cascade. To further examine whether STAT3 binds to the promoter region of PLGF, Chip assay was used and it was found that OSM could bind with PLGF promoter, which was inhibited by JAK3 and PI3K inhibitors. Accumulation of PLGF in the pannus may contribute to the inflammation, angiogenesis and joints destruction in RA patients. These findings demonstrated the important role of OSM in the pathology network of RA and provided novel therapeutic drug targets for RA treatment.

Propofol mediates signal transducer and activator of transcription 3 activation and crosstalk with phosphoinositide 3-kinase/AKT

“…Of interest, adenosine and classical ischemic preconditioning have been shown to induce crosstalk 30 , 31 . Our results are in accordance with those of Tu et al who showed that expression of a dominant-negative AKT or inhibition of PI3K with LY294002 decreased STAT3 phosphorylation at both tyr705 and ser727 residues in response to oncostatin M, a cytokine of the STAT3 activating interleukin-6 family 32 . Whether propofol activates STAT3 as a single event at level of plasma membrane or via receptor internalization that links with prosurvival PI3K-AKT signaling is the subject of ongoing investigation by our laboratory.…”

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

“…5b). The latter observation is consistent with a recent study which showed that STAT3 activity induces PlGF gene expression in synovial fibroblasts [44]. Inhibition of the NF-jB activity induced a delayed increase of the PlGF gene expression under control conditions (Fig.…”

Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

“…Fibroblasts are also a source of PlGF in other pathological conditions such as rheumatoid arthritis [26]. In addition to fibroblasts, PlGF expression has also been detected in cultured endothelial cells whereas monocyte/macrophage lineage cells are not known to produce PlGF [27].…”