免疫細胞の炎症性サイトカイン産生に対する選択的セロトニン再取り込み阻害薬の抑制効果

<p>Sepsis is a systemic inflammatory syndrome triggered by infections. Controlling the abnormal cytokine-producing pathology (cytokine storms) that contributes to the severity of sepsis is thought to be an effective treatment, but there is no specific drug for this as yet. Recently, there have been many reports that antidepressants, selective serotonin reuptake inhibitors (SSRIs), have anti-inflammatory effects. In fact, some SSRIs are in clinical trials for application in the treatment of some inflammatory diseases. In this study, to clarify the usefulness of SSRIs as "cytokine storm inhibitors," we aimed to elucidate their effects on the production of inflammatory cytokines (interleukin-6; IL-6) in immune cells. In murine macrophages and dendritic cells, SSRIs significantly suppressed IL-6 production induced by Toll-like receptor 3 (TLR3), TLR4 or TLR9 agonist, but not by TLR7 agonist. In murine lymphocytes, SSRIs also suppressed IL-6 production induced by T cell activator. According to a comparison of five SSRIs, fluoxetine, which is a potent inhibitor of IL-6 production and has low toxicity, was considered the most desirable SSRI as a cytokine storm inhibitor. An examination of the structural requirements indicated that the nucleophilicity of the N atom of fluoxetine has a critical role in anti-inflammatory effect. Overall, our findings suggest that SSRIs, especially fluoxetine, may represent an unprecedented cytokine storm inhibitor with a multifaceted anti-inflammatory effect.</p>