Shiraishi Hiroshi, Yoshida Hideyuki, Saeki Kazuko, Miura Yoshiki, Watanabe Satoko, Ishizaki Takuma, Hashimoto Masayuki, Takaesu Giichi, Kobayashi Takashi, Yoshimura Akihiko
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Int Immunol. 2008 Sep;20(9):1219-29. doi: 10.1093/intimm/dxn078. Epub 2008 Jul 17.
Dendritic cells (DCs) are specialized antigen-presenting cells that play pivotal roles in initiating immune responses. However, DC maturation is usually strongly restricted by the stromal microenvironment, especially in non-lymphoid tissues, such as skin and mucosa. Although suppression of DC maturation by stromal cells has been well documented, the molecular basis of this suppression has not been established. In this study, we examined the role of fibroblasts for DC maturation in vitro. The mouse embryonic fibroblasts (MEFs) strongly suppressed LPS-induced DC maturation. Although suppression of class II MHC and CD40 required DC-MEF contact, soluble factors in the culture supernatant of MEFs were sufficient for the suppression of IL-12 and tumor necrosis factor-alpha production. Using molecular-size selection and HPLC, we determined that prostaglandin E2 (PGE2) is a major soluble inhibitory factor secreted by MEFs. This was confirmed by the fact that cyclooxygenase inhibitors inhibited the production of the suppressive factor by MEFs. These results suggest that PGE2 is a major soluble factor produced by MEFs for the suppression of inflammatory cytokine production from DCs, while a contact mechanism between MEFs and DCs is required for the suppression to induce T cell-stimulating molecules.
树突状细胞（DCs）是一类特殊的抗原呈递细胞，在启动免疫反应中发挥关键作用。然而，DC的成熟通常受到基质微环境的强烈限制，尤其是在非淋巴组织中，如皮肤和黏膜。尽管基质细胞对DC成熟的抑制作用已有充分记载，但这种抑制作用的分子基础尚未明确。在本研究中，我们检测了成纤维细胞在体外对DC成熟的作用。小鼠胚胎成纤维细胞（MEFs）强烈抑制脂多糖（LPS）诱导的DC成熟。虽然II类主要组织相容性复合体（MHC）和CD40的抑制需要DC与MEF接触，但MEF培养上清中的可溶性因子足以抑制白细胞介素-12（IL-12）和肿瘤坏死因子-α（TNF-α）的产生。通过分子大小筛选和高效液相色谱法（HPLC），我们确定前列腺素E2（PGE2）是MEFs分泌的主要可溶性抑制因子。环氧化酶抑制剂抑制MEFs产生抑制因子这一事实证实了这一点。这些结果表明，PGE2是MEFs产生的主要可溶性因子，用于抑制DC产生炎性细胞因子，而MEF与DC之间的接触机制是抑制诱导T细胞刺激分子所必需的。
