Involvement of p38 MAP kinase in lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and prostaglandin E2 in human choriodecidua

Abstract

Chorioamnionitis is implicated in the pathogenesis of preterm delivery. However, the detailed mechanisms by which infection induces preterm labor are not well understood. This study has assessed the involvement of mitogen-activated protein (MAP) kinases in lipopolysaccharide (LPS)-induced pro- and anti-inflammatory cytokine and prostaglandin (PG) production in human choriodecidua. Samples of choriodecidua were collected before the onset of labor from women undergoing elective cesarean sections at term for breech presentation, previous cesarean delivery or cephalopelvic disproportion. Concentrations of TNFalpha, IL-10, PGE(2) and PGF(2)alpha in culture supernatants were measured by ELISA. Expression of COX-2 protein was analyzed by Western blotting. In human choriodecidual explants, LPS induced TNFalpha and IL-10 production in a dose- and time-dependent manner. LPS also up-regulated COX-2 expression and PG synthesis. Phosphorylations of extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, and c-Jun N-terminal kinases (JNK) were also confirmed by Western blotting. Furthermore, the effect of MAPK inhibitors was examined on LPS-induced pro- and anti-inflammatory cytokines and PG synthesis. Among the MAPK inhibitors examined, the p38 MAPK inhibitor, SB202190, significantly suppressed LPS-induced cytokine and PG production. SB202190 most profoundly suppressed the TNFalpha to IL-10 ratio, demonstrating that p38 MAPK inhibitor reduced predominantly TNFalpha other than IL-10 production. Phospho-p38 MAPK immunostaining was intense in extravillous trophoblast cells. The p38 MAPK seems to be most involved in signaling mechanisms when infection and inflammation cause preterm labor through PG synthesis. Novel therapeutic modalities targeting p38 MAPK may prevent to arrest preterm labor.

N,N-Dimethylacetamide Significantly Attenuates LPS- and TNFα-Induced Proinflammatory Responses Via Inhibition of the Nuclear Factor Kappa B Pathway

“…It is not surprising then to see that SB202190 was able to suppress secretion of these inflammatory cytokines and mediators. Shoji et al previously reported involvement of the MAPK pathway in the production of proinflammatory cytokines in the choriodecidua (55)(56)(57). What was unexpected was that BAY 11-7082, an NF-κB inhibitor, did not have a significant effect on the secretion of these cytokines in results, together with our cell viability assays, served as the basis for using 10 mM as the highest concentration in the in vitro experiments here.…”

Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes

“…Its similar potency to TPCA-1 in the ovine explant model would argue against the latter hypothesis. To date, no studies have characterised the expression and activity patterns of MAPKs during inflammation in human gestational membranes, although MAPKs are known to respond to infectious stimuli and regulate the production of pro-inflammatory cytokines (Underwood et al 2000, Barone et al 2001, Ward et al 2001, Ju et al 2002, Shoji et al 2007. Regardless, our results highlighted SB239063 as a potentially effective anti-inflammatory agent useful for preventing inflammation-driven PTB.…”

An in vitro investigation of the actions of reproductive hormones on the cervix of the ewe in the follicular stage: The effects of 17β-estradiol, oxytocin, FSH, and arachidonic acid on the cervical pathway for the synthesis of prostaglandin E2

“…In fact, PKA can phosphorylate diverse transcription factors leading to the synthesis of mRNAs for several target genes, including COX-2 [31]. The FSH signaling pathway can also diverge, at the level of PKA to activate other downstream targets such as the extracellular-regulated kinases and p38 MAPK (mitogen-activated protein kinases) in the MAPK signaling pathways [32,33], as has been observed in human chorion-decidua [34] and myometrial smooth muscle cells [35]. However, the existence of several alternative pathways through which FSH could stimulate the expression of COX-2 does not explain its failure to increase the concentration of PGE 2 in the culture media.…”