Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide.
Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide.
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DOI：
10.4049/jimmunol.162.11.6811
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发表时间：
1999-06
影响因子：
4.4
通讯作者：
D. Mullins;C. J. Burger;K. D. Elgert
中科院分区：
文献类型：
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作者：
D. Mullins;C. J. Burger;K. D. Elgert
肿瘤诱导的巨噬细胞(Mphis)部分地通过增加抑制T细胞反应的因子的产生和正调节细胞因子的产生不足来调节免疫抑制。紫杉醇可部分逆转肿瘤诱导的Mphi抑制活性，提示紫杉醇可恢复肿瘤宿主(TBH)Mphi的免疫前因子的产生。由于紫杉醇具有模拟内毒素的能力，并增加了内毒素诱导的免疫刺激细胞因子IL-12的产生，因此我们研究了紫杉醇是否诱导Mphi IL-12的产生。肿瘤生长通过选择性失调IL-12p40的表达，显著下调Mphi IL-12p70的产生。内毒素刺激不能克服肿瘤诱导的p40表达异常。相反，紫杉醇在体外显著促进正常宿主和TBH Mphi IL-12 p70的产生，尽管TBH Mphi IL-12的产生低于类似处理的正常宿主Mphi。紫杉醇以剂量依赖的方式促进p40的表达。通过重组Mphi IL-12的表达，紫杉醇可减轻肿瘤诱导的Mphi对T细胞同种反应性的抑制。阻断Mphi-NO可抑制紫杉醇诱导IL-12的产生。这表明紫杉醇诱导的活动可能涉及NO介导的自分泌诱导途径。综上所述，这些数据表明，紫杉醇恢复了脑出血患者IL-12的产生，并将其归因于NO的多效性，这是一种新的免疫治疗成分。通过诱导IL-12的产生，紫杉醇可能有助于纠正肿瘤诱导的免疫功能障碍。
Tumor-induced macrophages (Mphis) mediate immunosuppression, in part, through increased production of factors that suppress T cell responsiveness and underproduction of positive regulatory cytokines. Pretreatment of tumor-bearing host (TBH) Mphis with the anticancer agent paclitaxel (Taxol) partially reverses tumor-induced Mphi suppressor activity, suggesting that paclitaxel may restore TBH Mphi production of proimmune factors. Because paclitaxel demonstrates LPS-mimetic capabilities and increased production of the LPS-induced immunostimulatory cytokine IL-12 could account for enhanced T cell responsiveness, we investigated whether paclitaxel induces Mphi IL-12 production. Tumor growth significantly down-regulated Mphi IL-12 p70 production through selective dysregulation of IL-12 p40 expression. LPS stimulation failed to overcome tumor-induced dysregulation of p40 expression. In contrast, paclitaxel significantly enhanced both normal host and TBH Mphi IL-12 p70 production in vitro, although TBH Mphi IL-12 production was lower than that of similarly treated normal host Mphis. Paclitaxel enhanced p40 expression in a dose-dependent manner. Through reconstituted Mphi IL-12 expression, paclitaxel pretreatment relieved tumor-induced Mphi suppression of T cell alloreactivity. Blocking Mphi NO suppressed paclitaxel's ability to induce IL-12 production. This suggests that paclitaxel-induced activities may involve a NO-mediated autocrine induction pathway. Collectively, these data demonstrate that paclitaxel restores IL-12 production in the TBH and ascribe a novel immunotherapeutic component to the pleiotropic activities of NO. Through its capacity to induce IL-12 production, paclitaxel may contribute to the correction of tumor-induced immune dysfunction.