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.
MeSH terms
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Abortion, Spontaneous / drug therapy*
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Abortion, Spontaneous / etiology
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Abortion, Spontaneous / prevention & control
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Animals
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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CARD Signaling Adaptor Proteins
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Caspase 1 / genetics
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Caspase 1 / metabolism
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Cytokines / blood*
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Female
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Fetal Weight / drug effects
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Immune System Diseases / prevention & control
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Inflammasomes / metabolism
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Inflammation / etiology
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Lipopolysaccharides / toxicity
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Mice
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NLR Family, Pyrin Domain-Containing 3 Protein / genetics
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NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
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Peptides / genetics
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Peptides / metabolism
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Peptides / pharmacology
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Peptides / therapeutic use*
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Placenta / metabolism
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Pregnancy
Substances
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Anti-Inflammatory Agents
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Cytokines
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Inflammasomes
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Peptides
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Pycard protein, mouse
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preimplantation factor, mouse
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preimplantation factor, synthetic
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Caspase 1
Associated data
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ClinicalTrials.gov/NCT02239562
Grants and funding
The work was supported by a research grant from the Università Cattolica del Sacro Cuore (D1, 2014) and by Istituto Scientifico Internazionale, Paolo VI Institute, Università Cattolica del Sacro Cuore, Rome, Italy. Dr. Eytan R. Barnea is the (uncompensated) Chief Scientist for BioIncept, LLC. BioIncept, LLC did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.