VIP modulates the pro-inflammatory maternal response inducing tolerance to trophoblast-cells

L. FRACCAROLI; J. ALFIERI; L. LAROCCA; M. CALAFAT; V. ROCA; E. LOMBARDI; R. RAMHORST; C. PÉREZ LEIRÓS

BRITISH JOURNAL OF PHARMACOLOGY

Published by Wiley-Blackwell

Lugar: Edinburgh; Año: 2009 p. 116 - 126

0007-1188

Background and purpose: Successful embryo implantation occurs followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. VIP (vasoactive intestinal peptide) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favors embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory response and trophoblast-maternal leukocyte interaction. Experimental Approach: We tested VIP effects directly on immortalized trophoblast cells (Swan 71) and after co culture with maternal fertile PBMCs as representative models of feto-maternal dialogue. We also performed co-cultures of maternal and paternal PBMCs to test endogenous VIP effects on the systemic maternal alloresponse. Key results: Swan 71 cells express VPAC1 receptor and VIP induced their proliferation and the expression of leukaemia inhibitor factor (LIF), a proimplantatory marker. After the interaction with trophoblast cells, VIP increased Foxp3, the frequency of CD4+CD25+Foxp3+ within maternal PBMCs and TGF expression. In accordance, during the trophoblast-maternal PBMCs dialogueue, VIP reduced pro-inflammatory mediators (IL-6, MCP-1, nitric oxide) while increased IL-10. Moreover, trophoblast cells produced VIP which dose-dependently suppressed allomaternal response associated with a reduction of T-bet expression. Conclusions and implications: VIP induced pro-implantatory markers and trophoblast cell proliferation while it controlled the initial pro-inflammatory response increasing maternal Tregs and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two relevant strategies involving a direct trophic effect on trophoblast cells and an immunomodulatory effect that favors tolerance to fetal antigens.