Prostaglandin E2 induces the final maturation of IL-12-deficient CD1a+CD83+ dendritic cells: the levels of IL-12 are determined during the final dendritic cell maturation and are resistant to further modulation.
Prostaglandin E2 induces the final maturation of IL-12-deficient CD1a+CD83+ dendritic cells: the levels of IL-12 are determined during the final dendritic cell maturation and are resistant to further modulation.
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DOI：
10.4049/jimmunol.161.6.2804
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发表时间：
1998-09
影响因子：
4.4
通讯作者：
P. Kalinski;J. Schuitemaker;C. Hilkens;M. Kapsenberg
中科院分区：
文献类型：
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作者：
P. Kalinski;J. Schuitemaker;C. Hilkens;M. Kapsenberg
外周组织中未成熟树突状细胞 (DC) 的激活会诱导其迁移至淋巴结并成熟为 CD83+ DC，从而能够启动初始 T 细胞。炎症细胞因子IL-1β和TNF-α诱导成熟的DC，其可以分泌IL-12并促进Th0/Th1偏向细胞的发育。尚未描述具有 Th2 促进功能的 DC 成熟因子。在这里，我们表明，PGE2 虽然本身不会诱导最终的 DC 成熟，但它与 IL-1beta 和 TNF-α 具有协同作用，并且可以在浓度低 100 倍的情况下发挥作用。虽然在表型上与单独存在高浓度 IL-1β 和 TNF-α 时成熟的 DC 相同，但在额外存在 PGE2 的情况下成熟的 DC 显示出 IL-12 产生受损，并且幼稚 Th 细胞偏向于 Th2 发育。 DC 产生 IL-12 的能力也受到 IL-10 的抑制，与 PGE2 不同，IL-10 会抑制 DC 的成熟。在最终 DC 成熟期间建立的产生 IL-12 能力的差异在去除调节因子后是稳定的。重要的是，完全成熟的 DC 对 PGE2 和 IL-10 不敏感。这表明成熟DC与淋巴结内Th细胞相互作用时体内IL-12产生的水平主要是在外周组织中未成熟DC阶段预先确定的。这些数据暗示病原体引起的局部炎症反应的特征可以“指示”局部DC启动Th1或Th2偏向的反应。
Activation of immature dendritic cells (DC) in peripheral tissues induces their migration to lymph nodes and their maturation into CD83+ DC, which are able to prime naive T cells. The inflammatory cytokines IL-1beta and TNF-alpha induce mature DC, which can secrete IL-12 and promote the development of Th0/Th1-biased cells. DC maturation factors with a Th2-promoting function have not been described. Here we show that PGE2, although it does not induce final DC maturation by itself, synergizes with IL-1beta and TNF-alpha, and allows their effectiveness at 100-fold lower concentrations. While being phenotypically identical with the DC matured in the presence of high concentrations of IL-1beta and TNF-alpha alone, DC matured in the additional presence of PGE2 show impaired IL-12 production and bias naive Th cell development toward the Th2. The ability of DC to produce IL-12 is also suppressed by IL-10, which in contrast to PGE2, inhibits their maturation. The differences in the ability to produce IL-12, established during the final DC maturation, are stable after the removal of modulatory factors. Importantly, fully mature DC become unsusceptible to PGE2 and IL-10. This indicates that the levels of IL-12 production in vivo, in mature DC interacting with Th cells within the lymph nodes, are mainly predetermined at the stage of immature DC in peripheral tissues. These data imply that the character of pathogen-induced local inflammatory reaction can "instruct" local DC to initiate Th1 or Th2-biased responses.