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Pregnancy-Specific Down-Regulation of NF-B Expression in T Cells in Humans Is Essential for the Maintenance of the Cytokine Profile Required for Pregnancy Success¹

Perinatal Research, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, Sydney, New South Wales, Australia

It is accepted that human pregnancy is associated with a shift away from Th1 type and a bias toward Th2-type immune responses. The molecular mechanisms that regulate this shift are as yet unknown. We assessed the expression and activity of NF-B, a transcription factor that plays a central role in regulating immune responses. We isolated T cells from PBMCs from nonpregnant and pregnant females and demonstrated that the NF-B/IB signaling pathway is down-regulated in T cells in pregnancy. Using Western blotting, high levels of NF-B (p65) were detected in all nuclear fractions of T cells from nonpregnant females. In contrast, low levels of p65 were detected in nuclear fractions from T cells from pregnant females. Levels of IB and - were also higher in cytoplasmic fractions from T cells from nonpregnant than from pregnant females. The reduction in p65 levels in pregnancy was reflected in the activity of NF-B in EMSA; T cells from pregnant females contain less active NF-B than from nonpregnant females. Stimulation of T cells from nonpregnant females with PMA/ionomycin resulted in IB degradation, p65 translocation, and subsequent production of the Th1 cytokines IFN- and IL-2. In contrast, PMA stimulation had no effect on NF-B activity in T cells from pregnant females, and this was reflected in reduced Th1 cytokine production. Using the inhibitor of NF-B activity, SN50, we were able to show that NF-B activity was essential for the production of Th1 cytokines, suggesting that specific down-regulation of NF-B in T cells throughout gestation is paramount to pregnancy success through specific regulation of cytokine production.

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