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首页> 外文期刊>Journal of inflammation. >Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis
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Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis

机译：JAK1 / JAK3抑制剂CP-690,550介导的大鼠佐剂诱导的关节炎的抗炎活性和中性粒细胞减少

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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, dose-dependent 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 all of these parameters to pre-disease levels. The plasma concentration of CP-690,550 at efficacious doses was above the in vitro whole blood IC50 of JAK1 and JAK3 inhibition, but not that of JAK2. Conclusion Results from this investigation suggest that CP-690,550 is a potent inhibitor of JAK1 and JAK3 with potentially reduced cellular potency for JAK2. In rat AIA, as in the case of human RA, PBNC were decreased at efficacious exposures of CP-690,550. Inflammatory end points were similarly reduced, as judged by attenuation of paw edema and cytokines IL-6 and IL-17. Plasma concentration at these exposures was consistent with inhibition of JAK1 and JAK3 but not JAK2. Decreases in PBNC following CP-690,550 treatment may thus be related to attenuation of inflammation and are likely not due to suppression of granulopoiesis through JAK2 inhibition.
机译：背景技术酪氨酸激酶的Janus激酶（JAK）家族包括JAK1，JAK2，JAK3和TYK2，并且是通过I型和II型细胞因子受体进行信号传递所必需的。 CP-690,550是一种有效且选择性的JAK抑制剂，目前正用于类风湿关节炎（RA）和其他自身免疫性疾病适应症的临床试验中。在RA试验中，使用CP-690,550治疗观察到中性粒细胞计数（PBNC）呈剂量依赖性降低。进行这些研究是为了更好地理解CP-690,550处理后观察到的JAK选择性与PBNC降低之间的关系。方法在一组体外试验中评估了CP-690,550对小鼠，大鼠和人JAK的效力和选择性。还使用菌落形成试验在体外评估了CP-690,550对祖细胞粒细胞生成的影响。在体内，在大鼠佐剂诱发的关节炎（AIA）模型中评估了口服CP-690,550对关节炎（爪水肿），血浆细胞因子，PBNC和骨髓分化的效力。结果CP-690,550尽管在体外酶法测定中以nM效能抑制了所有四种JAK亚型，但在细胞测定法中仍有效抑制JAK1和JAK3的信号传导，其选择性是JAK2的5-100倍。用CP-690,550治疗可在体内观察到剂量依赖性的爪水肿抑制作用。在AIA疾病的背景下，血浆细胞因子（IL-6和IL-17），PBNC和骨髓骨髓祖细胞升高。在有效暴露下，CP-690,550将所有这些参数恢复到疾病前的水平。有效剂量下的CP-690,550血浆浓度高于JAK1和JAK3抑制的体外全血IC50，但不超过JAK2。结论该研究的结果表明CP-690,550是JAK1和JAK3的有效抑制剂，可能会降低JAK2的细胞效力。在大鼠AIA中，如同在人类RA中一样，在有效暴露于CP-690,550时PBNC降低。根据爪水肿和细胞因子IL-6和IL-17的减弱判断，炎症终点也有类似的降低。这些暴露时的血浆浓度与抑制JAK1和JAK3一致，但与抑制JAK2一致。因此，CP-690,550处理后PBNC的减少可能与炎症减轻有关，并且可能不是由于通过JAK2抑制而抑制了粒细胞生成。

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