Varas Alberto, Hernández-López Carmen, Valencia Jaris, Mattavelli Silvia, Martínez Victor G, Hidalgo Laura, Gutiérrez-Frías Cruz, Zapata Agustín G, Sacedón Rosa, Vicente Angeles
Department of Cell Biology, Faculty of Medicine, Ciudad Universitaria, Complutense University, Madrid, Spain.
J Leukoc Biol. 2008 Jun;83(6):1476-83. doi: 10.1189/jlb.1107792. Epub 2008 Mar 11.
The Hedgehog (Hh) family of signaling molecules functions in the development of numerous tissues during embryogenesis and has also been involved in adult self-renewing tissues. Recent results have demonstrated that the different components of the Hh signaling pathway are expressed in the human thymus. In this study, we investigate whether thymic dendritic cells (DCs) are cell targets for Hh signaling. Both components of the Hh receptor, Patched and Smoothened, as well as other Hh-binding proteins with modulating functions, are expressed by human thymic DCs. The expression of Gli1, Gli2, and Gli3 transcription factors suggests that the Hh signaling pathway is active in thymic DCs, and approximately one-half of thymic DCs produces Sonic Hh (Shh). The culture of thymic DCs with Shh protects them from apoptosis [similarly to CD40 ligand (CD40L)], and these antiapoptotic effects are related to an up-regulation of Bcl-2 and Bcl-X(L) protein expression. The addition of the Hh pathway inhibitor, cyclopamine, decreases DC viability and impairs their allostimulatory function in vitro. In addition, the blockade of the Hh signaling pathway by cyclopamine treatment abrogates the up-regulation of HLA-DR, CD86, CD80, and CD83 expression induced by CD40L on thymic DCs. Finally, we also show that after activation with CD40L thymic DCs down-regulate the expression of Hh receptor components as well as Shh production. Taken together, these results suggest that the survival and function of thymic DCs are regulated by an autocrine Hh signaling.
刺猬信号分子家族（Hh）在胚胎发育过程中的多种组织发育中发挥作用，并且也与成体自我更新组织有关。最近的研究结果表明，Hh信号通路的不同组分在人类胸腺中表达。在本研究中，我们调查胸腺树突状细胞（DCs）是否是Hh信号的细胞靶点。Hh受体的两个组分，即Patched和Smoothened，以及其他具有调节功能的Hh结合蛋白，均在人类胸腺DCs中表达。Gli1、Gli2和Gli3转录因子的表达表明Hh信号通路在胸腺DCs中是活跃的，并且大约一半的胸腺DCs产生音猬因子（Shh）。用Shh培养胸腺DCs可保护它们免于凋亡[类似于CD40配体（CD40L）]，并且这些抗凋亡作用与Bcl-2和Bcl-X(L)蛋白表达的上调有关。添加Hh通路抑制剂环杷明可降低DCs的活力并损害其体外异源刺激功能。此外，用环杷明处理阻断Hh信号通路可消除CD40L诱导的胸腺DCs上HLA-DR、CD86、CD80和CD83表达的上调。最后，我们还表明，用CD40L激活后，胸腺DCs会下调Hh受体组分的表达以及Shh的产生。综上所述，这些结果表明胸腺DCs的存活和功能受自分泌Hh信号的调节。
