title: Regulated suppression of NF-κB throughout pregnancy maintains a favourable cytokine environment necessary for pregnancy success.
abstract: Th1 immune responses are suppressed in pregnancy, but the temporal regulation and the mechanism(s) underlying this immune alteration are unknown. We assessed the expression of Th1 cytokines IFNγ, IL-2 and TNFα in response to stimulation in isolated T-cells from pregnant women throughout gestation. Using flow cytometry we demonstrated an early and sustained reduction in IFNγ and IL-2 production in CD3+ T-cells, but TNFα levels are not reduced until the third trimester. We assessed the expression of NF-κB and T-bet, transcription factors that play a central role in Th1 immune responses, throughout pregnancy. In isolated T-cells levels of available p65 were suppressed early in pregnancy, but T-bet expression was suppressed only in the third trimester. In contrast to p65, T-bet expression was transcriptionally regulated, with diminished T-bet mRNA in third-trimester samples. Re-expression of p65 in T-cells from third-trimester pregnant women resulted in an induction of T-bet expression in response to PMA stimulation and a concomitant increase in the production of IL-2 and IFNγ. The suppressive effect of pregnancy was ameliorated as early as 72h post-partum when p65 levels returned to normal as did the level of inducible IFNγ and IL-2. TNFα levels in post-partum women were significantly increased relative to non-pregnant controls. The pregnancy-specific suppression of p65 and subsequent loss of cytokine production suggest that this transcription factor acts specifically to regulate the cytokine environment that is required for pregnancy success.
authors.affiliation: Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St. Leonards, NSW, Australia.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Hadfield
authors.forename: Sharon A
authors.initials: SA
authors.lastname: McCracken
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ashton
authors.forename: Tue G
authors.initials: TG
authors.lastname: Nguyen
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Morris
mesh_terms: D000328:Adult; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics; D011264:Pregnancy Trimesters; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D058408:Th1-Th2 Balance; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor