Tumour-derived prostaglandin E2 and transforming growth factor-β synergize to inhibit plasmacytoid dendritic cell-derived interferon-α
Tumour-derived prostaglandin E2 and transforming growth factor-β synergize to inhibit plasmacytoid dendritic cell-derived interferon-α
复制标题
DOI：
10.1111/j.1365-2567.2009.03134.x
复制
发表时间：
2009-11-01
期刊：
影响因子：
6.4
通讯作者：
Hartmann, Gunther
中科院分区：
文献类型：
--
作者：
Bekeredjian-Ding, Isabelle;Schafer, Meike;Hartmann, Gunther
在以前的研究中，我们报道了浸润头颈部癌组织的浆细胞样树突状细胞（PDC）功能受损，但功能缺陷的分子基础尚不清楚。本研究表明，肿瘤源性前列腺素E2 （PGE(2)）和转化生长因子β (tgf - β)可增加白细胞介素8 (IL-8)，但协同抑制toll样受体7 （TLR7）和toll样受体9 （TLR9）刺激的PDC中干扰素α (ifn - α)和肿瘤坏死因子（TNF）的产生。PGE(2)的抑制作用可以通过诱导环AMP （cAMP）和环加氧酶抑制剂来模拟。tgf - β拮抗剂SB-431542证实了肿瘤源性tgf - β的作用。抑制肿瘤源性PGE(2)和tgf - β可恢复tlr诱导的PDC的ifn - α生成。此外，PGE(2)-和tgf - β处理的PDC表现出“耐受性”表型，因为CD40的下调伴随着CD86的上调。最后，在tlr刺激的PDC中，PGE(2)和tgf - β降低了CCR7: CXCR4比率，表明PDC迁移到肿瘤引流淋巴结的能力受损，但保留在表达基质细胞衍生因子1 （SDF-1）的组织中。基于这些数据，环加氧酶抑制剂和tgf - β拮抗剂可能改善基于TLR7和tlr9的肿瘤免疫治疗。
P>In previous studies we reported that plasmacytoid dendritic cells (PDC) infiltrating head and neck cancer tissue are functionally impaired, but the molecular basis for the functional deficiency remained unclear. Here we demonstrate that tumour-derived prostaglandin E2 (PGE(2)) and transforming growth factor-beta (TGF-beta) increase interleukin-8 (IL-8) but synergistically inhibit interferon-alpha (IFN-alpha) and tumour necrosis factor (TNF) production of Toll-like receptor 7 (TLR7)- and Toll-like receptor 9 (TLR9)-stimulated PDC. The inhibitory effect of PGE(2) could be mimicked by the induction of cyclic AMP (cAMP) and by inhibitors of cyclooxygenase. The contribution of tumour-derived TGF-beta was confirmed by the TGF-beta antagonist SB-431542. Suppression of tumour-derived PGE(2) and TGF-beta restored TLR-induced IFN-alpha production of PDC. Additionally, PGE(2)- and TGF-beta-treated PDC display a 'tolerogenic' phenotype because of a downregulation of CD40 accompanied by an upregulation of CD86. Finally, in TLR-stimulated PDC, PGE(2) and TGF-beta reduce the CCR7 : CXCR4 ratio, suggesting that PDC are impaired in their ability to migrate to tumour-draining lymph nodes but are retained in stromal cell-derived factor 1 (SDF-1)-expressing tissues. Based on these data, cyclooxygenase inhibitors and TGF-beta antagonists may improve TLR7- and TLR9-based tumour immunotherapy.