tailieunhanh - Báo cáo y học: "Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthriti"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài: Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. | Meyer et al. Journal of Inflammation 2010 7 41 http content 7 1 41 JOURNAL OF INFLAMMATION RESEARCH Open Access Anti-inflammatory activity and neutrophil reductions mediated by the JAK1 JAK3 inhibitor CP-690 550 in rat adjuvant-induced arthritis 1 11 2 1 1 Debra M Meyer Michael I Jesson Xiong Li Mollisa M Elrick Christie L Funckes-Shippy James D Warner Cindy J Gross2 Martin E Dowty3 Shashi K Ramaiah2 Jeffrey L Hirsch1 Matthew J Saabye1 Jennifer L Barks1 Nandini Kishore1 Dale L Morris2 Abstract Background The Janus kinase JAK family of tyrosine kinases includes JAK1 JAK2 JAK3 and TYK2 and is required for signaling through Type I and Type II cytokine receptors. CP-690 550 is a potent and selective JAK inhibitor currently in clinical trials for rheumatoid arthritis RA and other autoimmune disease indications. In RA trials dosedependent decreases in neutrophil counts PBNC were observed with CP-690 550 treatment. These studies were undertaken to better understand the relationship between JAK selectivity and PBNC decreases observed with CP-690 550 treatment. Methods Potency and selectivity of CP-690 550 for mouse rat and human JAKs was evaluated in a panel of in vitro assays. The effect of CP-690 550 on granulopoiesis from progenitor cells was also assessed in vitro using colony forming assays. In vivo the potency of orally administered CP-690 550 on arthritis paw edema plasma cytokines PBNC and bone marrow differentials were evaluated in the rat adjuvant-induced arthritis AIA model. Results CP-690 550 potently inhibited signaling through JAK1 and JAK3 with 5-100 fold selectivity over JAK2 in cellular assays despite inhibiting all four JAK isoforms with nM potency in in vitro enzyme assays. Dose-dependent inhibition of paw edema was observed in vivo with CP-690 550 treatment. Plasma cytokines IL-6 and IL-17 PBNC and bone marrow myeloid progenitor cells were elevated in the context of AIA disease. At efficacious exposures CP-690 550 returned .