TPL2 kinase regulates the inflammatory milieu of the myeloma niche
TPL2 kinase regulates the inflammatory milieu of the myeloma niche
复制标题
DOI：
10.1182/blood-2014-02-554071
复制
发表时间：
2014-05-22
期刊：
影响因子：
20.3
通讯作者：
Asimakopoulos, Fotis
中科院分区：
文献类型：
--
作者：
Hope, Chelsea;Ollar, Samuel J.;Asimakopoulos, Fotis
微环境调控通路的靶向调控对于控制骨髓瘤和其他基因/克隆异质性癌症可能是必不可少的。在此，我们报道了人类骨髓瘤相关单核/巨噬细胞(MAM)，而不是骨髓瘤浆细胞，构成了诊断时白细胞介素1β(IL-1β)、IL-10和肿瘤坏死因子-α的主要来源，而IL-6来自基质细胞和巨噬细胞。为了剖析MAM激活/细胞因子途径，我们分析了Toll样受体(TLR)在人骨髓瘤CD14(+)细胞中的表达。我们观察到TLR2和TLR6表达的共同调节与VERSICAN的局部处理相关，VERSICAN是一种与肿瘤进展相关的蛋白多糖TLR2/6激动剂。Verscan还没有从机制上与骨髓瘤的发病机制有关。我们推测VERSICAN-TLR2/6通路中最容易接近的靶点是丝裂原激活蛋白3(MAP3)激酶Tpl2(Cot/MAP3K8)。在体内基因工程骨髓瘤模型V kappa*MYC中，切除Tpl2导致与浆细胞生长缺陷相关的疾病潜伏期延长。在新生的骨髓瘤病变中，TPL2缺失消除了MAM中的“炎症开关”，并允许已建立的肿瘤中的巨噬细胞复极化。浆细胞中MYC的激活/表达与Tpl2活性无关。药物对人单核细胞Tpl2的抑制导致对TLR2刺激的IL-1β诱导/分泌的剂量依赖性减弱。我们的结果强调了依赖TLR2/6的Tpl2通路是通过巨噬细胞非自主作用来控制骨髓瘤进展的新的治疗靶点。
Targeted modulation of microenvironmental regulatory pathways may be essential to control myeloma and other genetically/clonally heterogeneous cancers. Here we report that human myeloma-associated monocytes/macrophages (MAM), but not myeloma plasma cells, constitute the predominant source of interleukin-1 beta (IL-1 beta), IL-10, and tumor necrosis factor-alpha at diagnosis, whereas IL-6 originates from stromal cells and macrophages. To dissect MAM activation/cytokine pathways, we analyzed Toll-like receptor (TLR) expression in human myeloma CD14(+) cells. We observed coregulation of TLR2 and TLR6 expression correlating with local processing of versican, a proteoglycan TLR2/6 agonist linked to carcinoma progression. Versican has not been mechanistically implicated in myeloma pathogenesis. We hypothesized that the most readily accessible target in the versican-TLR2/6 pathway would be the mitogen-activated protein 3 (MAP3) kinase, TPL2 (Cot/MAP3K8). Ablation of Tpl2 in the genetically engineered in vivo myeloma model, V kappa*MYC, led to prolonged disease latency associated with plasma cell growth defect. Tpl2 loss abrogated the "inflammatory switch" in MAM within nascent myeloma lesions and licensed macrophage repolarization in established tumors. MYC activation/expression in plasma cells was independent of Tpl2 activity. Pharmacologic TPL2 inhibition in human monocytes led to dose-dependent attenuation of IL-1 beta induction/secretion in response to TLR2 stimulation. Our results highlight a TLR2/6-dependent TPL2 pathway as novel therapeutic target acting nonautonomously through macrophages to control myeloma progression.