Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success.

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-kappaB, 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-kappaB/IkappaB signaling pathway is down-regulated in T cells in pregnancy. Using Western blotting, high levels of NF-kappaB (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 IkappaBalpha and -beta 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-kappaB in EMSA; T cells from pregnant females contain less active NF-kappaB than from nonpregnant females. Stimulation of T cells from nonpregnant females with PMA/ionomycin resulted in IkappaBalpha degradation, p65 translocation, and subsequent production of the Th1 cytokines IFN-gamma and IL-2. In contrast, PMA stimulation had no effect on NF-kappaB activity in T cells from pregnant females, and this was reflected in reduced Th1 cytokine production. Using the inhibitor of NF-kappaB activity, SN50, we were able to show that NF-kappaB activity was essential for the production of Th1 cytokines, suggesting that specific down-regulation of NF-kappaB in T cells throughout gestation is paramount to pregnancy success through specific regulation of cytokine production.