Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4
Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4
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DOI：
10.4049/jimmunol.174.5.3032
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发表时间：
2005-03-01
影响因子：
4.4
通讯作者：
López-Collazo, E
中科院分区：
文献类型：
--
作者：
del Fresno, C;Otero, K;López-Collazo, E
尽管血液单核细胞对肿瘤细胞具有显着的细胞毒活性，但肿瘤浸润单核细胞通常在癌症患者中失活。预暴露于肿瘤细胞的单核细胞显示 TNF-α、IL-12p40 和 IL-IR 相关激酶 (IRAK)-1 的表达水平显着降低。 Ser/Thr 激酶 IRAK-1 的激活是多种炎症过程中的重要事件。相比之下，IRAK 家族的另一个成员 IRAK-M 负向调节该途径，并且在耐受内毒素的单核细胞培养物和耐受时间内脓毒症患者的单核细胞中上调。在这项研究中，我们发现在肿瘤细胞存在的情况下培养的人单核细胞中，IRAK-M 的 mRNA 和蛋白质水平表达增强。在与不同的肿瘤细胞以及固定的肿瘤细胞和补充有来自肿瘤细胞培养物的上清液的培养基共培养后，IRAK-M在单核细胞中被诱导。此外，慢性粒细胞白血病患者和转移患者的血液单核细胞也过度表达IRAK-M。低浓度的透明质酸（肿瘤细胞释放的一种细胞表面糖胺聚糖）也会上调 IRAK-M。通过与抗CD44或抗TLR4阻断抗体一起温育，透明质酸和肿瘤细胞对IRAK-M的诱导被消除。此外，IRAK-M特异性小干扰RNA下调IRAK-M表达可恢复重新暴露于肿瘤细胞系的人单核细胞中的TNF-α mRNA表达和蛋白质产生。总而言之，我们的研究结果表明，在肿瘤细胞存在的情况下，人类单核细胞的失活涉及 IRAK-M 的上调，并且这种效应似乎是由透明质酸通过 CD44 和 TLR4 的结合介导的。
Although blood monocytes possess significant cytotoxic activity against tumor cells, tumor-infiltrating monocytes are commonly deactivated in cancer patients. Monocytes pre-exposed to tumor cells show significantly decreased expression levels of TNF-alpha, IL-12p40, and IL-IR-associated kinase (IRAK)-1. Activation of the Ser/Thr kinase IRAK-1 is an important event in several inflammatory processes. By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance. In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells. IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures. Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M. Low concentrations of hyaluronan, a cell surface glycosaminoglycan released by tumor cells, also up-regulated IRAK-M. The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line. Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4.