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Changes in the Th1:Th2 cytokine bias in pregnancy and the effects of the anti-inflammatory cyclopentenone prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J2.

Sykes L, MacIntyre DA, Yap XJ, Ponnampalam S, Teoh TG, Bennett PR - Mediators Inflamm. (2012)

Bottom Line: The anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-Prostaglandin J(2) (15dPGJ(2)) 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.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. 15dPGJ(2) reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2(+ve) cells. 15dPGJ(2) also reduced phospho-p65 in stimulated PBMCs.In summary, 15dPGJ(2) 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.

View Article: PubMed Central - PubMed

Affiliation: Parturition Research Group, Department of Surgery and Cancer, Institute of Reproduction and Developmental Biology, Imperial College London, W120NN London, UK.

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-Δ(12,14)-Prostaglandin J(2) (15dPGJ(2)) 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 15dPGJ(2) 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 15dPGJ(2) 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. 15dPGJ(2) reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2(+ve) cells. 15dPGJ(2) also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ(2) 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.

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CRTH2 expression in lymphocytes derived from nonpregnant and pregnant subjects. Lymphocytes were gated according to forward scatter and side scatter and T helper cells were identified using CD4 as a cell surface marker (n = 8 for each group). A representative cytogram from a woman of 28-week gestation is presented with the right upper quadrant showing CRTH2+/CD4+ lymphocytes (a). The percentage of CRTH2 positive T helper cells (presented as a percentage of positive CD4 positive cells) increased slightly in the third trimester, although statistical significance was not reached (b). No change in mean fluorescence intensity was detected in either the nonpregnant or pregnant samples (c). For statistical analysis ANOVA with Dunnett's multiple comparison test with NP as a control was used.
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fig2: CRTH2 expression in lymphocytes derived from nonpregnant and pregnant subjects. Lymphocytes were gated according to forward scatter and side scatter and T helper cells were identified using CD4 as a cell surface marker (n = 8 for each group). A representative cytogram from a woman of 28-week gestation is presented with the right upper quadrant showing CRTH2+/CD4+ lymphocytes (a). The percentage of CRTH2 positive T helper cells (presented as a percentage of positive CD4 positive cells) increased slightly in the third trimester, although statistical significance was not reached (b). No change in mean fluorescence intensity was detected in either the nonpregnant or pregnant samples (c). For statistical analysis ANOVA with Dunnett's multiple comparison test with NP as a control was used.

Mentions: To determine whether the Th2 response in pregnancy is reflected by an increase in the percentage of CRTH2 positive cells, we used CD4 as a marker of T helper cells and calculated the percentage these cells that express CRTH2 (Figure 2(a)). The percentage of CRTH2 positive cells in the CD4 positive population was observed to increase in the second trimester of pregnancy from 2.24% in nonpregnant women to 3.12% at 28 weeks before reducing to 2.75% at term and 2.4% in term labour, although statistical significance was not reached (Figure 2(b)). There was no significant increase in the mean fluorescence intensity of CRTH2 in T helper cells between nonpregnant and pregnant subjects (Figure 2(c)), although a slight increase in CRTH2 production was noted in term labouring samples (P = 0.15).


Changes in the Th1:Th2 cytokine bias in pregnancy and the effects of the anti-inflammatory cyclopentenone prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J2.

Sykes L, MacIntyre DA, Yap XJ, Ponnampalam S, Teoh TG, Bennett PR - Mediators Inflamm. (2012)

CRTH2 expression in lymphocytes derived from nonpregnant and pregnant subjects. Lymphocytes were gated according to forward scatter and side scatter and T helper cells were identified using CD4 as a cell surface marker (n = 8 for each group). A representative cytogram from a woman of 28-week gestation is presented with the right upper quadrant showing CRTH2+/CD4+ lymphocytes (a). The percentage of CRTH2 positive T helper cells (presented as a percentage of positive CD4 positive cells) increased slightly in the third trimester, although statistical significance was not reached (b). No change in mean fluorescence intensity was detected in either the nonpregnant or pregnant samples (c). For statistical analysis ANOVA with Dunnett's multiple comparison test with NP as a control was used.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368617&req=5

fig2: CRTH2 expression in lymphocytes derived from nonpregnant and pregnant subjects. Lymphocytes were gated according to forward scatter and side scatter and T helper cells were identified using CD4 as a cell surface marker (n = 8 for each group). A representative cytogram from a woman of 28-week gestation is presented with the right upper quadrant showing CRTH2+/CD4+ lymphocytes (a). The percentage of CRTH2 positive T helper cells (presented as a percentage of positive CD4 positive cells) increased slightly in the third trimester, although statistical significance was not reached (b). No change in mean fluorescence intensity was detected in either the nonpregnant or pregnant samples (c). For statistical analysis ANOVA with Dunnett's multiple comparison test with NP as a control was used.
Mentions: To determine whether the Th2 response in pregnancy is reflected by an increase in the percentage of CRTH2 positive cells, we used CD4 as a marker of T helper cells and calculated the percentage these cells that express CRTH2 (Figure 2(a)). The percentage of CRTH2 positive cells in the CD4 positive population was observed to increase in the second trimester of pregnancy from 2.24% in nonpregnant women to 3.12% at 28 weeks before reducing to 2.75% at term and 2.4% in term labour, although statistical significance was not reached (Figure 2(b)). There was no significant increase in the mean fluorescence intensity of CRTH2 in T helper cells between nonpregnant and pregnant subjects (Figure 2(c)), although a slight increase in CRTH2 production was noted in term labouring samples (P = 0.15).

Bottom Line: The anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-Prostaglandin J(2) (15dPGJ(2)) 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.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. 15dPGJ(2) reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2(+ve) cells. 15dPGJ(2) also reduced phospho-p65 in stimulated PBMCs.In summary, 15dPGJ(2) 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.

View Article: PubMed Central - PubMed

Affiliation: Parturition Research Group, Department of Surgery and Cancer, Institute of Reproduction and Developmental Biology, Imperial College London, W120NN London, UK.

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-Δ(12,14)-Prostaglandin J(2) (15dPGJ(2)) 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 15dPGJ(2) 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 15dPGJ(2) 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. 15dPGJ(2) reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2(+ve) cells. 15dPGJ(2) also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ(2) 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.

Show MeSH
Related in: MedlinePlus