Fiumara P, Snell V, Li Y, Mukhopadhyay A, Younes M, Gillenwater A M, Cabanillas F, Aggarwal B B, Younes A
Department of Lymphoma and Myeloma, Head and Neck Surgery, and Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2001 Nov 1;98(9):2784-90. doi: 10.1182/blood.v98.9.2784.
The malignant Hodgkin and Reed-Sternberg (H/RS) cells of Hodgkin disease (HD) express several members of the tumor necrosis factor (TNF) receptor family, including CD30 and CD40, and secrete several cytokines and chemokines. However, little is known about what regulates cytokine and chemokine secretion in H/RS cells. Although H/RS cells are predominantly of B-cell origin, they frequently share phenotypic and functional features with dendritic cells (DCs). Previous studies reported that receptor activator of nuclear factor kappaB (NF-kappaB) (RANK), a member of the TNF receptor family, is expressed on DCs, and that RANK ligand (RANKL) enhances DC survival and induces them to secrete cytokines. This study reports that, similar to DCs, cultured H/RS cells expressed RANK. However, unlike DCs, H/RS cells also expressed RANKL. Soluble RANKL activated NF-kappaB and induced messenger RNA expression of interferon-gamma, interleukin-8 (IL-8), IL-13, IL-9, IL-15, and RANTES, in addition to the receptors for IL-9, IL-13, IL-15, and CCR4. RANKL increased IL-8 and IL-13 levels in the supernatants of H/RS cell lines, an effect that was blocked by soluble RANK. Furthermore, soluble RANK decreased the basal level of IL-8 in one cell line, suggesting that IL-8 was induced by an autocrine RANKL/RANK loop. RANKL had no effect on H/RS cell survival in culture, and it did not modulate the expression of bcl-2, bcl-xL, bax, or inhibitors of apoptosis proteins. These data provide evidence of further functional similarities between DCs and H/RS cells. The coexpression of RANK and RANKL in H/RS cells suggests that they may regulate cytokine and chemokine secretion in H/RS cells by an autocrine mechanism.
霍奇金淋巴瘤（HD）的恶性霍奇金和里德-斯腾伯格（H/RS）细胞表达肿瘤坏死因子（TNF）受体家族的多个成员，包括CD30和CD40，并分泌多种细胞因子和趋化因子。然而，对于H/RS细胞中细胞因子和趋化因子分泌的调节机制知之甚少。尽管H/RS细胞主要起源于B细胞，但它们常与树突状细胞（DC）具有共同的表型和功能特征。先前的研究报道，TNF受体家族成员核因子κB受体激活剂（NF-κB）（RANK）在DC上表达，且RANK配体（RANKL）可增强DC的存活并诱导其分泌细胞因子。本研究报道，与DC相似，培养的H/RS细胞表达RANK。然而，与DC不同的是，H/RS细胞也表达RANKL。可溶性RANKL激活NF-κB，并诱导γ干扰素、白细胞介素-8（IL-8）、IL-13、IL-9、IL-15和调节激活正常T细胞表达和分泌因子（RANTES）的信使核糖核酸表达，以及IL-9、IL-13、IL-15和CCR4的受体表达。RANKL增加了H/RS细胞系上清液中IL-8和IL-13的水平，可溶性RANK可阻断这一效应。此外，可溶性RANK降低了一个细胞系中IL-8的基础水平，提示IL-8是由自分泌的RANKL/RANK环路诱导产生的。RANKL对培养的H/RS细胞存活无影响，也不调节bcl-2、bcl-xL、bax或凋亡蛋白抑制剂的表达。这些数据提供了DC与H/RS细胞之间存在进一步功能相似性的证据。H/RS细胞中RANK和RANKL的共表达提示，它们可能通过自分泌机制调节H/RS细胞中细胞因子和趋化因子的分泌。
