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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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Effect of 15dPGJ2 on Th1 and Th2 cytokines. Peripheral blood mononuclear cells were incubated with vehicle control or 32 μM of 15dPGJ2 and stimulated with PMA/ionomycin before being gated on the lymphocyte population according to forward and side scatter. A representative 28-week patient sample is presented with CD4+/IFN-γ+ cells shown in the right upper quadrant (a). A representative histogram reveals a clear shift to the right upon stimulation indicative of increased IFN-γ producing cells (b). This effect was attenuated with 15dPGJ2 pre-treatment. PMA/ionomycin induced IFN-γ and TNF-α production was decreased with 15dPGJ2 treatment (c) and (d); however, levels of IL-4 remained unchanged. No change in IL-4 producing cells was detected (e). For statistical analysis a Student's t-test was used to compare means between paired treated and nontreated samples; **P < 0.01 and *P < 0.05.
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fig3: Effect of 15dPGJ2 on Th1 and Th2 cytokines. Peripheral blood mononuclear cells were incubated with vehicle control or 32 μM of 15dPGJ2 and stimulated with PMA/ionomycin before being gated on the lymphocyte population according to forward and side scatter. A representative 28-week patient sample is presented with CD4+/IFN-γ+ cells shown in the right upper quadrant (a). A representative histogram reveals a clear shift to the right upon stimulation indicative of increased IFN-γ producing cells (b). This effect was attenuated with 15dPGJ2 pre-treatment. PMA/ionomycin induced IFN-γ and TNF-α production was decreased with 15dPGJ2 treatment (c) and (d); however, levels of IL-4 remained unchanged. No change in IL-4 producing cells was detected (e). For statistical analysis a Student's t-test was used to compare means between paired treated and nontreated samples; **P < 0.01 and *P < 0.05.

Mentions: 15dPGJ2 is an anti-inflammatory PG and a ligand for CRTH2. We therefore explored the effect of 15dPGJ2 on the Th1 cytokines, IFN-γ and TNF-α. To do this, cells were preincubated with 32 μM of 15dPGJ2 or vehicle control prior to the addition of PMA/ionomycin before intracellular cytokines were detected by flow cytometry (Figures 3(a) and 3(b)). 15dPGJ2 reduced the production of PMA/ionomycin stimulated IFN-γ production (measured as mean fluorescence intensity) in T helper cells from 101.9 to 53 (P < 0.01) in nonpregnant controls, 115.7 to 52.4 (P < 0.01) in 28 week samples and from 110 to 60.7 in term (P < 0.01) samples. There was a nonsignificant decrease observed in term labouring samples also (88.3 to 66.3, Figure 3(c)). Similarly, a significant decrease in PMA/ionomycin-induced TNF-α production following treatment with 15dPGJ2 was detected in all pregnant samples assessed (Figure 3(d)).


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)

Effect of 15dPGJ2 on Th1 and Th2 cytokines. Peripheral blood mononuclear cells were incubated with vehicle control or 32 μM of 15dPGJ2 and stimulated with PMA/ionomycin before being gated on the lymphocyte population according to forward and side scatter. A representative 28-week patient sample is presented with CD4+/IFN-γ+ cells shown in the right upper quadrant (a). A representative histogram reveals a clear shift to the right upon stimulation indicative of increased IFN-γ producing cells (b). This effect was attenuated with 15dPGJ2 pre-treatment. PMA/ionomycin induced IFN-γ and TNF-α production was decreased with 15dPGJ2 treatment (c) and (d); however, levels of IL-4 remained unchanged. No change in IL-4 producing cells was detected (e). For statistical analysis a Student's t-test was used to compare means between paired treated and nontreated samples; **P < 0.01 and *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368617&req=5

fig3: Effect of 15dPGJ2 on Th1 and Th2 cytokines. Peripheral blood mononuclear cells were incubated with vehicle control or 32 μM of 15dPGJ2 and stimulated with PMA/ionomycin before being gated on the lymphocyte population according to forward and side scatter. A representative 28-week patient sample is presented with CD4+/IFN-γ+ cells shown in the right upper quadrant (a). A representative histogram reveals a clear shift to the right upon stimulation indicative of increased IFN-γ producing cells (b). This effect was attenuated with 15dPGJ2 pre-treatment. PMA/ionomycin induced IFN-γ and TNF-α production was decreased with 15dPGJ2 treatment (c) and (d); however, levels of IL-4 remained unchanged. No change in IL-4 producing cells was detected (e). For statistical analysis a Student's t-test was used to compare means between paired treated and nontreated samples; **P < 0.01 and *P < 0.05.
Mentions: 15dPGJ2 is an anti-inflammatory PG and a ligand for CRTH2. We therefore explored the effect of 15dPGJ2 on the Th1 cytokines, IFN-γ and TNF-α. To do this, cells were preincubated with 32 μM of 15dPGJ2 or vehicle control prior to the addition of PMA/ionomycin before intracellular cytokines were detected by flow cytometry (Figures 3(a) and 3(b)). 15dPGJ2 reduced the production of PMA/ionomycin stimulated IFN-γ production (measured as mean fluorescence intensity) in T helper cells from 101.9 to 53 (P < 0.01) in nonpregnant controls, 115.7 to 52.4 (P < 0.01) in 28 week samples and from 110 to 60.7 in term (P < 0.01) samples. There was a nonsignificant decrease observed in term labouring samples also (88.3 to 66.3, Figure 3(c)). Similarly, a significant decrease in PMA/ionomycin-induced TNF-α production following treatment with 15dPGJ2 was detected in all pregnant samples assessed (Figure 3(d)).

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