Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds

Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease

“…OSM has been therapeutically targeted in rheumatoid arthritis (RA) through the neutralization of OSM, and the inhibition of the JAK/STAT pathway 59, 60 . JAK inhibitors CP-690,550 and INCB028050, which inhibit JAK-1, JAK-2 and JAK-3, were shown to effectively block the activation of STAT1, STAT3 and STAT5 in OSM-treated fibroblasts in vitro 60 . In contrast, a phase II trial in rheumatoid arthritis (RA) using an anti-OSM monoclonal antibody, GSK315234, did not show any benefit of blocking OSM, potentially due to low affinity OSM binding.…”

The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis

“…It is widely believed that influencing the JAK/ /STAT pathway may turn out to be a promising therapeutic target, especially in the case of multidirectional impact on different elements of the signaling cascade [24]. Selective blocking of a single kinase, e.g.…”

“…The JAK3-selective inhibitor PF-956980 suppressed STAT1/-5 activation, but did not affect STAT3. The JAK inhibitors CP-690 550 and INCB028050 both suppressed the activation of JAK1/-2/-3 and downstream STAT1/-3/-5, as well as the expression levels of target proinflammatory genes (MCP-I, SAA1/2) in oncostatin-M (OSM)-stimulated rheumatoid synovial fibroblasts [24]. Novel protein kinase specific may be targeted as a dual protein kinase inhibitor, such as the newly described N1-p-fluorobenzyl-cymserine, which is reported to inhibit both p38 kinase and NF-κB [9].…”

Cryptotanshinone induces reactive oxygen species‑mediated apoptosis in human rheumatoid arthritis fibroblast‑like synoviocytes

“…The STAT3 signaling pathway is responsible for transmitting the outer signals of the cell to the nucleus and expressing the effects of biological stimulation through the induction of target gene transcription. Dysfunctional JAK/STAT signaling has been implicated in various hematological and immunological disorders, as well as other pathological inflammatory conditions (14)(15)(16). Reactive oxygen species (ROS), including oxygen ions, peroxides and oxygen-free radicals, are the main molecules that the body produces during oxidative stress.…”