Functional coexpression of Interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: Involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin's lymphoma
Functional coexpression of Interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: Involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin's lymphoma
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DOI：
10.1002/ijc.24389
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发表时间：
2009-09-01
影响因子：
6.4
通讯作者：
Aldinucci, Donatella
中科院分区：
文献类型：
--
作者：
Cattaruzza, Lara;Gloghini, Annunziata;Aldinucci, Donatella
经典型霍奇金淋巴瘤（cHL）的临床和病理特征反映了由于恶性Hodgkin-Reed-斯滕贝格（H-RS）细胞和/或周围反应性细胞产生多种细胞因子和趋化因子而引起的异常组织和全身免疫应答。在此，我们证明HL衍生的细胞系（L-428、KM-H2、HDLM-2、L-1236和L-540）和来自HL患者淋巴结组织的原代H-RS细胞表达IL-7（R）受体。IL-7似乎参与HL的自分泌回路，因为L-1236、HDLM-2和KM-H2细胞显示IL-7的组成性产生，中和抗IL-7抗体诱导其基础增殖的统计学显著抑制。此外，外源性或成纤维细胞来源的IL-7促进培养的H-RS细胞的克隆形成性生长并减少细胞凋亡，也能够部分保护这些细胞免受阿霉素的细胞毒性作用。我们还提供了证据表明，IL-7刺激IL-7受体表达的成纤维细胞从HL涉及的淋巴结（HLF）的IL-6分泌，并在HLF与L1236细胞的共培养物中可以观察到IL-6分泌的显着增加。最后，我们表明，L-1236细胞衍生的IL-7代表了纯化的CD 4 + CD 25 + CD 127 di（m/-）调节性T细胞（Tcells）增殖的共刺激因子。综上所述，我们的数据表明IL-7/IL-7 R轴构成了H-RS细胞与其反应性细胞背景之间的额外信号传导途径，从而影响肿瘤细胞的增殖和存活，作为THP扩增的辅因子并增强IL-6的微环境产生，IL-6是一种与HL患者中“B”症状和不良结局相关的细胞因子。(C)2009年UICC
The clinical and pathological features of classical Hodgkin lymphoma (cHL) mirror an abnormal tissue and systemic immune response due to the production of a variety of cytokines and chemokines by the malignant Hodgkin-Reed-Sternberg (H-RS) cells and/or surrounding reactive cells. Here, we demonstrate that HL-derived cell lines (L-428, KM-H2, HDLM-2, L-1236 and L-540) and primary H-RS cells from lymph node tissues of HL patients express the IL-7(R) receptor. IL-7 appears to be involved in autocrine circuitries of HL because L-1236, HDLM-2 and KM-H2 cells display the constitutive production of IL-7 and neutralizing anti-IL-7 antibodies induces a statistically significant inhibition of their basal proliferation. In addition, IL-7, either exogenous or fibroblasts-derived, promotes the clonogenic growth and reduces apoptosis of cultured H-RS cells, being also able to partially protect these cells from the cytotoxic effects of doxorubicin. We also provide evidence that IL-7 stimulates IL-6 secretion from IL-7R-expressing fibroblasts from HL-involved lymph nodes (HLFs), and that a striking increase in IL-6 secretion can be observed in cocultures of HLFs with L1236 cells. Finally, we show that L-1236 cells-derived IL-7 represents a costimulator for proliferation of purified CD4+CD25+CD127di(m/-) regulatory T cells (Tregs). Taken together, our data indicates that the IL-7/IL-7R axis constitutes an additional signaling pathway between H-RS cells and their reactive cellular background, thereby affecting proliferation and survival of tumor cells, acting as a cofactor for Tregs expansion and enhancing the microenviromental production of IL-6, a cytokine associated with the presence of "B" symptoms and a poor outcome in HL patients. (C) 2009 UICC