Zhang Maomao, Zhang Shuo, Wu Jian, Sun Yong, Li Lili, Du Wenjuan, Liu Jingjin, Hou Jingbo, Yu Bo
The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang Province, China ; Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
PLoS One. 2013 Jun 26;8(6):e66336. doi: 10.1371/journal.pone.0066336. Print 2013.
Protosappanin A (PrA), an immunosuppressive ingredient of the medicinal herb Caesalpinia sappan L, prolongs heart allograft survival in rats, possibly by impairing the function of antigen-presenting cells (APCs). We examined the effects of PrA on the maturation and function of dendritic cells (DCs), a potent class of APCs, and the downstream cell-cell and intracellular signaling pathways mediating the immunosuppressive activity of PrA. PrA inhibited LPS-stimulated maturation of Wistar rat DCs in vitro as reflected by reduced expression of costimulatory molecules (CD80 and CD86) and reduced expression of TLR4 and NF-κB, two critical signaling components for antigen recognition. PrA also enhanced the release of IL-10 and decreased the release of IL-12 from DCs, but had no effect on the production of TGF-ß. In mixed cultures, Wistar DCs pretreated with PrA impaired the proliferation of Sprague Dawley (SD) rat T cells while promoting the expansion of SD rat CD4(+)CD25(+) regulatory T cells (Tregs). Both oral PrA treatment and infusion of PrA-pretreated Wistar DCs prolonged cardiac allograft survival (Wistar donor, SD recipient) and expanded recipient CD4(+)CD25(+)Foxp3(+) Tregs. Donor spleen cells, but not spleen cells from a third rat strain (DA), supported the expansion of recipient CD4(+)CD25(+)Foxp3(+) Tregs and suppressed recipient T cell proliferation. We conclude that PrA triggers a tolerogenic state in DCs that allows for the induction of alloantigen-specific Tregs and the suppression of allograft rejection in vivo.
原苏木素A（PrA）是药用植物苏木的一种免疫抑制成分，它可能通过损害抗原呈递细胞（APC）的功能来延长大鼠心脏同种异体移植的存活时间。我们研究了PrA对树突状细胞（DC）（一种强大的APC）成熟和功能的影响，以及介导PrA免疫抑制活性的下游细胞间和细胞内信号通路。PrA在体外抑制了Wistar大鼠DC受LPS刺激后的成熟，这表现为共刺激分子（CD80和CD86）表达降低，以及抗原识别的两个关键信号成分TLR4和NF-κB表达降低。PrA还增强了DC释放IL-10，并减少了DC释放IL-12，但对TGF-β的产生没有影响。在混合培养中，用PrA预处理的Wistar DC损害了Sprague Dawley（SD）大鼠T细胞的增殖，同时促进了SD大鼠CD4(+)CD25(+)调节性T细胞（Treg）的扩增。口服PrA治疗和输注经PrA预处理的Wistar DC均延长了心脏同种异体移植的存活时间（Wistar供体，SD受体），并扩增了受体CD4(+)CD25(+)Foxp3(+) Treg。供体脾细胞，而非来自第三个大鼠品系（DA）的脾细胞，支持受体CD4(+)CD25(+)Foxp3(+) Treg的扩增并抑制受体T细胞增殖。我们得出结论，PrA在DC中引发了一种致耐受性状态，从而能够在体内诱导同种异体抗原特异性Treg并抑制同种异体移植排斥反应。
