Mullins D W, Burger C J, Elgert K D
Department of Biology, Microbiology and Immunology Section, Virginia Polytechnic Institute and State University, Blacksburg 24061, USA.
J Immunol. 1999 Jun 1;162(11):6811-8.
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.
肿瘤诱导的巨噬细胞（Mphis）部分通过增加抑制T细胞反应性的因子产生以及正调节细胞因子产生不足来介导免疫抑制。用抗癌药物紫杉醇（泰素）对荷瘤宿主（TBH）的Mphis进行预处理可部分逆转肿瘤诱导的Mphi抑制活性，这表明紫杉醇可能恢复TBH的Mphis产生促免疫因子的能力。由于紫杉醇具有模拟脂多糖（LPS）的能力，且LPS诱导的免疫刺激细胞因子白细胞介素-12（IL-12）产生增加可解释T细胞反应性增强，因此我们研究了紫杉醇是否诱导Mphi产生IL-12。肿瘤生长通过选择性失调IL-12 p40表达显著下调Mphi IL-12 p70的产生。LPS刺激未能克服肿瘤诱导的p40表达失调。相比之下，紫杉醇在体外显著增强了正常宿主和TBH的Mphis产生IL-12 p70的能力，尽管TBH的Mphis产生IL-12的能力低于经类似处理的正常宿主Mphis。紫杉醇以剂量依赖的方式增强p40表达。通过重建Mphi的IL-12表达，紫杉醇预处理减轻了肿瘤诱导的Mphi对T细胞同种异体反应性的抑制。阻断Mphi产生一氧化氮（NO）可抑制紫杉醇诱导IL-12产生的能力。这表明紫杉醇诱导的活性可能涉及NO介导的自分泌诱导途径。总的来说，这些数据表明紫杉醇可恢复TBH中IL-12的产生，并将一种新的免疫治疗成分归因于NO的多效性活性。通过其诱导IL-12产生的能力，紫杉醇可能有助于纠正肿瘤诱导的免疫功能障碍。
