Maternal control of inflammation is essential during pregnancy and an exaggerated response is one of the underlying causes of fetal loss. Inflammatory response is mediated by multiple factors and Toll-like receptors (TLRs) are central. Activation of TLRs results in NALP-3 mediated assembly of apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 into the inflammasome and production of pro-inflammatory cytokines IL-1β and IL-18. Given that preventing measures are lacking, we investigated PreImplantation Factor (PIF) as therapeutic option as PIF modulates Inflammation in pregnancy. Additionally, synthetic PIF (PIF analog) protects against multiple immune disorders. We used a LPS induced murine model of fetal loss and synthetic PIF reduced this fetal loss and increased the embryo weight significantly. We detected increased PIF expression in the placentae after LPS insult. The LPS induced serum and placenta cytokines were abolished by synthetic PIF treatment and importantly synthetic PIF modulated key members of inflammasome complex NALP-3, ASC, and caspase-1 as well. In conclusion our results indicate that synthetic PIF protects against LPS induced fetal loss, likely through modulation of inflammatory response especially the inflammasome complex. Given that synthetic PIF is currently tested in autoimmune diseases of non-pregnant subjects (clinicaltrials.gov, NCT02239562), therapeutic approach during pregnancy can be envisioned.

Di Simone, N., Di Nicuolo, F., Marana, R., Castellani, R., Ria, F., Veglia, M., Scambia, G., Surbek, D., Barnea, E., Mueller, M. .., Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response, <<PLOS ONE>>, 2017; (Jul 12;12(7):e0180642): 1-16. [doi:10.1371/journal.pone.0180642.] [http://hdl.handle.net/10807/104021]

Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response

Di Simone, Nicoletta
Primo
;
Marana, Riccardo;Castellani, Roberta;Ria, Francesco;Veglia, Manuela;Scambia, Giovanni;
2017

Abstract

Maternal control of inflammation is essential during pregnancy and an exaggerated response is one of the underlying causes of fetal loss. Inflammatory response is mediated by multiple factors and Toll-like receptors (TLRs) are central. Activation of TLRs results in NALP-3 mediated assembly of apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 into the inflammasome and production of pro-inflammatory cytokines IL-1β and IL-18. Given that preventing measures are lacking, we investigated PreImplantation Factor (PIF) as therapeutic option as PIF modulates Inflammation in pregnancy. Additionally, synthetic PIF (PIF analog) protects against multiple immune disorders. We used a LPS induced murine model of fetal loss and synthetic PIF reduced this fetal loss and increased the embryo weight significantly. We detected increased PIF expression in the placentae after LPS insult. The LPS induced serum and placenta cytokines were abolished by synthetic PIF treatment and importantly synthetic PIF modulated key members of inflammasome complex NALP-3, ASC, and caspase-1 as well. In conclusion our results indicate that synthetic PIF protects against LPS induced fetal loss, likely through modulation of inflammatory response especially the inflammasome complex. Given that synthetic PIF is currently tested in autoimmune diseases of non-pregnant subjects (clinicaltrials.gov, NCT02239562), therapeutic approach during pregnancy can be envisioned.
Inglese
Di Simone, N., Di Nicuolo, F., Marana, R., Castellani, R., Ria, F., Veglia, M., Scambia, G., Surbek, D., Barnea, E., Mueller, M. .., Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response, <>, 2017; (Jul 12;12(7):e0180642): 1-16. [doi:10.1371/journal.pone.0180642.] [http://hdl.handle.net/10807/104021]
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