Interleukin (IL)-6-type cytokines exert their effects through activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade. The JAK/STAT pathways play an important role in rheumatoid arthritis, since JAK inhibitors have exhibited dramatic effects on rheumatoid arthritis (RA) in clinical trials. In this study, we investigated the molecular effects of a small molecule JAK inhibitor, CP690,550 on the JAK/STAT signaling pathways and examined the role of JAK kinases in rheumatoid synovitis | Migita et al. Arthritis Research Therapy 2011 13 R72 http content 13 3 R72 RESEARCH ARTICLE Open Access CP690 550 inhibits oncostatin M-induced JAK STAT signaling pathway in rheumatoid synoviocytes Kiyoshi Migita Atsumasa Komori Takafumi Torigoshi Yumi Maeda Yasumori Izumi Yuka Jiuchi Taiichiro Miyashita Minoru Nakamura Satoru Motokawa and Hiromi Ishibashi Abstract Introduction Interleukin IL -6-type cytokines exert their effects through activation of the Janus kinase signal transducers and activators of transcription JAK STAT signaling cascade. The JAK STAT pathways play an important role in rheumatoid arthritis since JAK inhibitors have exhibited dramatic effects on rheumatoid arthritis RA in clinical trials. In this study we investigated the molecular effects of a small molecule JAK inhibitor CP690 550 on the JAK STAT signaling pathways and examined the role of JAK kinases in rheumatoid synovitis. Methods Fibroblast-like synoviocytes FLS were isolated from RA patients and stimulated with recombinant oncostatin M OSM . The cellular supernatants were analyzed using cytokine protein chips. IL-6 mRNA and protein expression were analyzed by real-time PCR method and ELISA respectively. Protein phosphorylation of rheumatoid synoviocytes was assessed by Western blot using phospho-specific antibodies. Results OSM was found to be a potent inducer of IL-6 in FLS. OSM stimulation elicited rapid phosphorylation of STATs suggesting activation of the JAK STAT pathway in FLS. CP690 550 pretreatment completely abrogated the OSM-induced production of IL-6 as well as OSM-induced JAK STAT and activation of mitogen-activated kinases MAPKs in FLS. Conclusions These findings suggest that IL-6-type cytokines contribute to rheumatoid synovitis through activation of the JAK STAT pathway in rheumatoid synoviocytes. Inhibition of these pro-inflammatory signaling pathways by CP690 550 could be important in the treatment of RA. Introduction Rheumatoid arthritis RA is a
