Cytotrophoblasts suppress macrophage-mediated inflammation through a contact-dependent mechanism.

ABSTRACT:

Problem

Gestational membrane (GM) infection provokes inflammation and can result in preterm prelabor rupture of membranes (PPROM). The choriodecidual layer of the GM includes decidual stromal cells (DSC), cytotrophoblasts (CTB), and macrophages (M?). Our laboratory has previously shown that DSCs suppress M? TNF-? production through secreted prostaglandin E₂ . We hypothesized that CTBs would also inhibit M? cytokine expression through secreted mediators.

Method of study

THP.1 M?-like cells with an NF-?B reporter construct or human blood monocyte-derived M? were co-cultured with the Jeg3 CTB cell line or primary human CTBs and challenged with group B streptococcus (GBS) or Toll-like receptor (TLR) agonists. Conditioned medium generated from CTB cultures was applied to M? cultures before infection or treatment. Alternatively, CTBs were co-incubated with, but physically separated from, M? and GBS or TLR-stimulated. NF-?B was assessed via alkaline phosphatase assay, and proinflammatory mediators were assessed by qRT-PCR and ELISA.

Results

CTBs suppressed GBS- or TLR-stimulated M? NF-?B activity, and TNF-? and MMP9 production. Direct physical contact between CTBs and M? was required for full immunosuppression. Immunosuppression could be overcome by increasing the ratio of M? to CTB.

Conclusions

CTBs limit M? NF-?B activation and production of TNF-? and MMP9 through an as-yet unknown, cell-to-cell contact-mediated mechanism. This suppression is distinct from the PGE₂ -mediated M? TNF-? suppression by DSC, suggesting that DSCs and CTBs regulate M? inflammation through distinct mechanisms. How M? integrates these signals in an intact GM will be paramount to determining causes and prevention of PPROM.

SUBMITTER: Eastman AJ 

PROVIDER: S-EPMC7897285 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature