Abstract
The non-canonical NF-κB signaling (RelB/p52) pathway drives pro-labor genes in the human placenta, including corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), making this a potential therapeutic target to delay onset of labor. Here we sought to identify small molecule compounds from a pre-existing chemical library of orally active drugs that can inhibit this NF-κB signaling, and in turn, human placental CRH and COX-2 production. We used a cell-based assay coupled with a dual-luciferase reporter system to perform an in vitro screening of a small molecule library of 1,120 compounds for inhibition of the non-canonical NF-κB pathway. Cell toxicity studies and drug efflux transport MRP1 assays were used to further characterize the lead compounds. We have found that 14 drugs have selective inhibitory activity against lymphotoxin beta complex-induced activation of RelB/p52 in HEK293T cells, several of which also inhibited expression of CRH and COX-2 in human term trophoblast. We identified sulfapyridine and propranolol with activity against CRH and COX-2 that deserve further study. These drugs could serve as the basis for development of orally active drugs to affect length of gestation, first in an animal model, and then in clinical trials to prevent preterm birth during human pregnancy.
Highlights
Preterm birth is arguably the greatest risk facing pregnant women and their newborns, and one of the greatest health problems facing the populations in the United States and countries around the world
A mixture of pGL4.32 and pRL-CMV vectors was transiently co-transfected into HEK293T cells. 48 hours later, the transfectants were exposed to individual compounds at a concentration of 20 μM for 2 hours, and 100 ng/mL lymphotoxin-α1β2 (LT-α1β2) for 4 hours
We have shown that the non-canonical NF-κB signaling pathway positively regulates pro-labor genes of human placental origin including corticotropin-releasing hormone (CRH) and COX-212,27, and may be a central regulator of the clock that governs length of pregnancy
Summary
Preterm birth is arguably the greatest risk facing pregnant women and their newborns, and one of the greatest health problems facing the populations in the United States and countries around the world. We have shown that the non-canonical NF-κB signaling pathway, functioning in human placenta under influence of glucocorticoids and progestins, regulates CRH and COX-210–13. The liberated p52 forms a heterodimer with RelB and subsequently translocates into the nucleus to regulate target genes Activation of this pathway may be triggered by a subset of TNF receptor family members, and in select tissues like activated B lymphocytes[15] and neurons[16], it may be constitutively active. Like plasma cells and select neurons, the non-canonical NF-κB pathway is constitutively activated in term cytotrophoblast under the persistent influence of glucocorticoid[10]
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