Induction of the IL-9 gene by HTLV-1 Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism
Induction of the IL-9 gene by HTLV-1 Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism
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DOI：
10.1182/blood-2007-09-113654
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发表时间：
2008-05-15
期刊：
影响因子：
20.3
通讯作者：
Waldmann, Thomas A.
中科院分区：
文献类型：
--
作者：
Chen, Jing;Petrus, Mike;Waldmann, Thomas A.
成人 T 细胞白血病 (ATL) 的病原体是人类 T 细胞嗜淋巴细胞病毒 1 型 (HTLV-1)。 HTLV-1 蛋白 Tax 改变基因表达，包括细胞因子及其受体的表达，这在 ATL 的早期阶段发挥着重要作用。在这里，我们证明白细胞介素 9 (IL-9) 的表达是由 Tax 通过其近端启动子中的 NF-kappa B 基序激活的，而 IL-9 受体-a 是通过其近端启动子中的 NF-kappa B 基序激活的。 (IL-9R α) 表达不是由 Tax 诱导的。然而，针对 IL-9R α 的中和单克隆抗体可抑制数名患者原代 ATL 细胞的离体自发增殖，这支持了 IL-9/IL-9R α 在 ATL 中的作用。对这些患者新鲜分离的外周血单核细胞进行荧光激活细胞分选仪分析，结果显示其表达 CD14 的单核细胞上有高水平的 IL-9Ra 表达。此外，来自这些患者的单独纯化的T细胞或单核细胞不会离体增殖，而这些细胞类型的混合物通过接触依赖性方式表现出显着的增殖。综上所述，我们的数据表明，原代 ATL 细胞通过 IL-9 支持表达 IL-9R α/CD14 的单核细胞的作用，从而支持恶性 T 细胞的离体自发增殖。总之，这些数据支持 IL-9 及其受体通过旁分泌机制在 ATL 中发挥作用。
The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type 1 (HTLV-1). The HTLV-1 protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-kappa B motif in its proximal promoter, whereas IL-9 receptor-a. (IL-9R alpha) expression is not induced by Tax. However, supporting a role for IL-9/IL-9R alpha in ATL, a neutralizing monoclonal antibody directed toward IL-9R alpha inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Ra on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9R alpha/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.