Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion
Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion
复制标题
DOI：
10.1182/blood-2008-05-155408
复制
发表时间：
2008-11-01
期刊：
影响因子：
20.3
通讯作者：
Dayer, Jean-Michel
中科院分区：
文献类型：
--
作者：
Chizzolini, Carlo;Chicheportiche, Rachel;Dayer, Jean-Michel
微环境分子线索直接T辅助细胞（Th）分化;然而，Th 17的命运决定在人类中仍然是不准确的理解。为了评估前列腺素E（2）（PGE（2））在Th扩增中的作用，我们通过CD 3交联激活外周血单个核细胞。在外源性PGE（2）存在的情况下，外周血单核细胞产生的白细胞介素-17（IL-17）、C-C趋化因子配体20（CCL 20）/巨噬细胞炎性蛋白3 α（MIP-3 α）、CXC趋化因子配体8（CXCL 8）/IL-8水平高于对照培养物，而干扰素-γ和IL-22水平低于对照培养物。外源性PGE（2）和IL-23在诱导IL-17方面具有协同作用，而吲哚美辛和IL-23阻断剂显著降低IL-17的产生，但不降低干扰素-γ的产生。此外，IL-1而不是肿瘤坏死因子是IL-17产生的绝对必要条件。PGE 2使产生IL-17的CD 4（+）T细胞的频率加倍，并且在CD 4（+）亚群中增强C-C趋化因子受体6（CCR 6）和CCR 4，同时降低CXC趋化因子受体3（CXCR 3）表达。此外，在CD 4（+）T细胞系中，IL-17的产生与CCR 6（+）亚群分离。与CXCR 3（+）Th细胞相比，CCR 6（+）存在时，单核细胞/巨噬细胞产生更高水平的基质金属蛋白酶-1、-3和-9，但CXCL 10和IL-1 β水平相似。这些结果表明PGE（2）和IL-23参与了具有高IL-17产生能力的CD 4（+）T细胞的扩增，这反过来又有利于单核细胞产生对宿主防御和组织破坏重要的介质。（血。2008; 112：3696-3703）
Microenvironment molecular cues direct T helper (Th) cell differentiation; however, Th17 fate determination is still imprecisely understood in humans. To assess the role of prostaglandin E(2) (PGE(2)) in Th expansion, we activated peripheral blood mononuclear cells by CD3 cross-linking. In the presence of exogenous PGE(2), peripheral blood mononuclear cells produced higher interleukin-17 (IL-17), C-C chemokine ligand 20 (CCL20)/macrophage inflammatory protein 3 alpha (MIP-3 alpha), CXC chemokine ligand 8 (CXCL8)/IL-8, and lower interferon-gamma and IL-22 levels than in control cultures. Exogenous PGE(2) and IL-23 synergized in inducing IL-17, whereas indomethacin and IL-23 blockade drastically reduced IL-17 but not interferon-gamma production. Furthermore, IL-1 but not tumor necrosis factor was absolutely required for IL-17 production. PGE2 doubled the frequency of CD4(+) T cells producing IL-17 and within the CD4(+) subset enhanced C-C chemokine receptor 6 (CCR6) and CCR4 while decreasing CXC chemokine receptor 3 (CXCR3) expression. Furthermore, in CD4(+) T-cell lines, the production of IL-17 segregated with the CCR6(+) subset. In the presence of CCR6(+) compared with CXCR3(+) Th cells, monocytes/macrophages produced much higher levels of matrix metalloproteinase-1, -3, and -9 but similar levels of CXCL10 and IL-1 beta. These results identify PGE(2) and IL-23 as participating in the expansion of CD4(+) T cells endowed with high IL-17 production capacity, which in turn favors monocyte production of mediators important for host defense and tissue destruction. (Blood. 2008; 112: 3696-3703)