Changes in the Th1 : Th2 Cytokine Bias in Pregnancy and the Effects of the Anti-Inflammatory Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-ProstaglandinJ2

Abstract

Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2) protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ12,14-Prostaglandin J2 (15dPGJ2) inhibits nuclear factor Kappa B (NF-κB) in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ2 could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4) synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs) from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ2 or vehicle control and stimulated with phorbol myristyl acetate (PMA)/ionomycin. The percentage of CD4+ cells producing interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ2 reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2+ve cells. 15dPGJ2 also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ2 suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL.

Women Serum Concentrations of the IL-10 Family of Cytokines and IFN-γ Decrease from the Third Trimester of Pregnancy to Active Labor

“…In this way, the concentrations of some members of the IL-10 family of cytokines decrease as the time for delivery approximates. Hence, these decreasing concentrations could be related to a change in the Th1 profile [4,37,38] . Despite other reports indicating a negative correlation between amniotic fluid IL-10 concentrations and gestational age at delivery [39] , our findings did not reveal such an association in serum samples.…”

Interleukin 4 inhibition as a potential therapeutic in pemphigus

“…This imbalance is the result of Th1 suppression rather than Th2 promotion [61,62]. Female patients, having pemphigus, exhibit deterioration of their disease in pregnancy period [63].…”

Murine model: maternal administration of stem cells for prevention of prematurity

“…49,50 Proper balance among proinflammatory, antiinflammatory, and regulatory cytokines provides self-tolerance and fetal tolerance and protects against pathogen invasion to avoid preterm birth and fetal inflammatory response syndrome. 51-54 The magnitude of the immune response towards inflammation is determined by the balance between antigen-driven activation of lymphocytes and regulatory influences that dampen the response.…”