Fraccaroli Laura, Alfieri Julio, Larocca Luciana, Calafat Mario, Roca Valeria, Lombardi Eduardo, Ramhorst Rosanna, Leirós Claudia Pérez
Immunopharmacology Laboratory, School of Sciences, University of Buenos Aires, Buenos Aires, Argentina.
Br J Pharmacol. 2009 Jan;156(1):116-26. doi: 10.1111/j.1476-5381.2008.00055.x.
Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions.
We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses.
Swan 71 cells express VPAC(1) receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor beta expression. Also, during the trophoblast-maternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet.
Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens.
胚胎成功着床后会引发局部促炎反应和Th1反应,随后由Th2反应控制。血管活性肠肽(VIP)具有抗炎作用,可促进耐受性/Th2反应,同时有利于胚胎发育。我们研究了VIP对人滋养层细胞、母体促炎反应以及滋养层-母体白细胞相互作用的潜在调节作用。
我们将VIP直接作用于滋养层细胞系(天鹅座71细胞),并与母体外周血单个核细胞(PBMC)共培养,以此作为母胎对话的模型来测试VIP的作用。我们还将母体和父体的PBMC共培养,以测试内源性VIP对母体同种异体反应的影响。
天鹅座71细胞表达VPAC(1)受体,VIP可诱导其增殖以及白血病抑制因子(一种着床前标志物)的表达。与滋养层细胞相互作用后,VIP增加了Foxp3、母体PBMC中CD4+CD25+Foxp3+细胞的比例以及转化生长因子β的表达。此外,在滋养层-母体PBMC相互作用过程中,VIP减少了促炎介质[白细胞介素(IL)-6、单核细胞趋化蛋白1、一氧化氮],同时增加了IL-10。滋养层细胞产生的VIP可剂量依赖性地抑制母体同种异体反应,同时T细胞转录因子T-bet的表达降低。
血管活性肠肽通过增加母体调节性T细胞和抗炎细胞因子,诱导着床前标志物和滋养层细胞增殖,同时控制初始促炎反应。作为一种自分泌调节肽,VIP可能通过两种机制促进胎儿存活;对滋养层细胞的直接营养作用以及有利于对胎儿抗原产生耐受性的免疫调节作用。