Fluoxetine and Citalopram Exhibit Potent Antiinflammatory Activity in Human and Murine Models of Rheumatoid Arthritis and Inhibit Toll-like Receptors
Fluoxetine and Citalopram Exhibit Potent Antiinflammatory Activity in Human and Murine Models of Rheumatoid Arthritis and Inhibit Toll-like Receptors
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DOI：
10.1002/art.27304
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发表时间：
2010-03-01
影响因子：
--
通讯作者：
Williams, Richard
中科院分区：
文献类型：
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作者：
Sacre, Sandra;Medghalchi, Mino;Williams, Richard
目标。据报道，选择性5-羟色胺再摄取抑制剂(SSRIs)除了具有抗抑郁作用外，还具有抗炎作用。本研究的目的是评价两种SSRIs，氟西汀和西酞普兰在小鼠胶原性关节炎(CIA)和人类类风湿关节炎(RA)体外疾病模型中的抗炎作用。在给予SSRIs治疗后，每天评估患有CIA的DBA/1小鼠的足爪肿胀和临床评分。治疗结束时，对关节结构进行组织学检查。培养的人RA滑膜用SSRIs处理，并测定细胞因子的产生。检测SSRIs对小鼠和人巨噬细胞、人B细胞和人成纤维样滑膜细胞的Toll样受体(Toll-like Receptor，TLR)功能的影响。两种SSRI都显著抑制了CIA小鼠的疾病进展，其中氟西汀在临床和组织学水平上显示出最大程度的疗效。此外，这两种药物都显著抑制了人RA滑膜培养中肿瘤坏死因子、白介素6和干扰素-γ诱导蛋白10的自发产生。氟西汀和西酞普兰还可抑制TLR3、7、8和9的信号转导，为其抗炎作用提供了可能的机制。氟西汀和西酞普兰治疗选择性地抑制内体TLR信号转导，改善CIA的疾病，并抑制人RA组织炎性细胞因子的产生。这些数据突出了SSRI药物家族的抗关节炎潜力，并提供了TLRs参与RA发病的进一步证据。SSRIs可能为潜在的抗关节炎药物开发提供模板。
Objective. Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA).Methods. Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs.Results. Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-gamma-inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action.Conclusion. Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development.