Expression and function of toll-like receptors in multiple myeloma patients: toll-like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor-κB
Expression and function of toll-like receptors in multiple myeloma patients: toll-like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor-κB
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DOI：
10.1111/j.1365-2141.2010.08284.x
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发表时间：
2010-09-01
影响因子：
6.5
通讯作者：
Wu, Depei
中科院分区：
文献类型：
--
作者：
Xu, Yang;Zhao, Yun;Wu, Depei
Toll样受体（TLR）是天然免疫的主要因子，其识别入侵的微生物产物并调节正常和恶性人类B淋巴细胞的生长。多发性骨髓瘤（MM）是一种克隆性浆细胞恶性肿瘤，尽管已有报道TLR对MM浆细胞的调节作用，但其分子机制尚不清楚。我们首先比较了MM患者和健康供体中TLR 1和TLR 10的转录本，发现患者骨髓单个核细胞（BMMC）中TLR 2、-4和-9的转录本高于供体;此外，流式细胞术分析表明，MM细胞中TLR 4和TLR 9的表达高于正常细胞。这两种TLR的配体能够促进MM细胞的生长并保护它们免受血清剥夺诱导的凋亡，但不能保护正常浆细胞，这可以用抗IL 6中和抗体或NF-κ B活性的阻断来减弱。进一步的研究表明，这些TLR配体可以触发NF-κ B p65的核转位，并且活化的NF-κ B足以增加MM细胞中IL 6转录本的表达。这些数据表明，活化的NF-κ B信号传导可能在TLR 4和TLR 9的配体促进MM细胞的生长和存活中起关键作用，部分通过IL 6自分泌。
P>Toll like receptors (TLRs) are the major agents for innate immunity that recognize invading microbial products and regulate the growth of normal and malignant human B lymphocytes. Multiple myeloma (MM) is a clonal plasma cell malignancy, though the regulatory role of TLRs in MM plasma cells has been reported, the molecular mechanism remains unclear. We first compared the transcripts of TLR1 to TLR10 in MM patients and healthy donors and found that TLR2, -4 and -9 transcripts were higher in bone marrow mononuclear cells (BMMCs) from patients than those from donors; in addition the expression of TLR4 and TLR9 were higher in MM cells than normal cells as demonstrated by flow cytometric analyses. The ligands of these two TLRs were capable to promote the growth of MM cells and protect them from serum-deprivation-induced apoptosis but not normal plasma cells, which could be attenuated with anti-IL6 neutralizing antibodies or blockage of NF-kappa B activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF-kappa B p65 and the activated NF-kappa B was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF-kappa B signalling probably plays a crucial role for the ligands of TLR4 and TLR9 to promote the growth and survival of MM cells partially through IL6 autocrine.