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Differential host response to LPS variants in amniochorion and the TLR4/MD-2 system in Macaca nemestrina.


ABSTRACT:

Objectives

Microbial-specific factors are likely critical in determining whether bacteria trigger preterm labor. Structural variations in lipopolysaccharide (LPS), a component of gram-negative bacteria, can determine whether LPS has an inflammatory (agonist) or anti-inflammatory (antagonist) effect through Toll-like receptor 4 (TLR4). Our objective was to determine whether amniochorion could discriminate between LPS variants in a nonhuman primate model. We also cloned Macaca nemestrina TLR4 and MD-2 and compared this complex functionally to the human homologue to establish whether nonhuman primates could be used to study TLR4 signaling in preterm birth.

Study design

Amniochorion explants from M. nemestrina were stimulated with a panel of LPS variants for 24 h. Supernatants were analyzed for IL-1beta, TNF-alpha, IL-6, IL-8 and prostaglandins E2 and F2alpha. Tissue expression of TLR1, 2, 4, 6, MyD88 and NF-kappaB was studied by RT-PCR. M. nemestrina TLR4 and MD-2 genes were cloned and compared with their human counterparts in a recombinant TLR4 signaling system to determine LPS sensitivity.

Results

LPS variants differentially stimulated cytokines and prostaglandins, which was not related to transcriptional changes of TLR4 or other TLRs. Nearly all elements of LPS binding and TLR4 leucine-rich repeats were conserved between humans and M. nemestrina. TLR4/MD-2 signaling complexes from both species were equally sensitive to LPS variants.

Conclusions

LPS variants elicit a hierarchical inflammatory response within amniochorion that may contribute to preterm birth. LPS sensitivity is similar between M. nemestrina and humans, validating M. nemestrina as an appropriate model to study TLR4 signaling in preterm birth.

SUBMITTER: Chang J 

PROVIDER: S-EPMC2934902 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Publications

Differential host response to LPS variants in amniochorion and the TLR4/MD-2 system in Macaca nemestrina.

Chang J J   Jain S S   Carl D J DJ   Paolella L L   Darveau R P RP   Gravett M G MG   Adams Waldorf K M KM  

Placenta 20100901 9


<h4>Objectives</h4>Microbial-specific factors are likely critical in determining whether bacteria trigger preterm labor. Structural variations in lipopolysaccharide (LPS), a component of gram-negative bacteria, can determine whether LPS has an inflammatory (agonist) or anti-inflammatory (antagonist) effect through Toll-like receptor 4 (TLR4). Our objective was to determine whether amniochorion could discriminate between LPS variants in a nonhuman primate model. We also cloned Macaca nemestrina T  ...[more]

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