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6.2 Atosiban activates NF-κB and pro-inflammatory pathways in human amnion via Gαi signalling
  1. SH Kim1,
  2. A Blanks2,
  3. S Thornton3,
  4. PR Bennett1,
  5. V Terzidou1
  1. 1Imperial College London, London, UK
  2. 2Warwick Medical School, Coventry, UK
  3. 3University of Exeter Medical School, Exeter, UK

Abstract

Inflammation is recognized as one of the key characteristics of both preterm and term labour. There is accumulating evidence suggesting that NF-κB plays a significant role in the physiology of human labour. NF-κB has been shown to increase in human amnion in association with labour. In term pre-labour amniocytes, OT couples with Gαi, but not Gαq, to induce sequential activation of MAPKs and NF-κB to increase expression of downstream pro-labour genes including PG synthetic enzymes and inflammatory cytokines/chemokines. We have previously reported that the OTR antagonist, atosiban, does not inhibit, but stimulates both MAPKs and NF-κB in amnion. Here, we investigate the downstream effects of NF-κB activation by atosiban and the relevant G protein coupling involved.

Following activation of MAPKs and NF-κB with atosiban stimulation, there were significant increases in mRNA expressions of NF-κB-regulated genes; IL-6, CCL5, and COX-2, and increases in the release of IL-6 and CCL5 after 2 h and 6 h, respectively (p < 0.05, ANOVA). In addition, upregulation of COX-2 and activation of cPLA2 were observed at protein level, as well as the subsequent PGE2 production (p < 0.05, ANOVA). Pretreatment with PTX reduced the effect of atosiban on NF-κB, ERK and p38 activation, and inhibited COX-2 and p-cPLA2 expression, indicating that these effects are mediated through Gαi (p < 0.05, ANOVA).

We conclude that atosiban induces activation of NF-κB and increase expression of downstream pro-labour genes via OTR- Gαi coupling. Therefore, therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider potential inflammatory activation by ligand-directed signalling.

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