Background: Preeclampsia is a pregnancy-specific disorder that continues to cause significant maternal and fetal morbidity and mortality due to our lack of understanding of its pathophysiology. Current evidence indicates that an increase in inflammatory cytokines, such as TNF-a and IL-6, resulting from placental oxidative stress stimulates placental production of the anti-angiogenic factors, sFlt1 and sEng. Recently, our group has shown that Activin A also plays a role in disease development as pregnant mice treated with Activin A develop preeclampsia-like symptoms. However, the relationship between Activin A and the other key factors in the development of preeclampsia is unknown. Aim: to determine the relationship between Activin A, anti-angiogenic factors and inflammatory cytokines. Hypothesis: TNF-a and IL-6 stimulates placental Activin A production, which in turn stimulates the placental production of sFlt1 and sEng in the pathophysiology of preeclampsia. Methods: Placental explants from healthy term pregnancies were cultured with either Xanthine/ Xanthine oxidase (X/XO), TNF-a, IL-6 or sFlt1 and sEng, and Activin A production was determined by ELISA and qPCR. sFlt1 and sEng production was also determined by ELISA in explants treated with Activin A. Results: Placental explants treated with X/XO showed a 3-fold increase in Activin A production (P<0.05). Explants treated with IL-6 also showed a similar 3-fold increase in placental Activin A production (P<0.05). However, sFlt1 and sEng treatment did not affect Activin A production by the placental explants (P>0.05). The production of sFlt1 and sEng by the explants were also not affected by Activin A treatment (P>0.05). Conclusion: These results suggest that during the development of preeclampsia, an increase in inflammatory cytokines, such as IL-6, resulting from placental oxidative stress stimulates the placental production of anti-angiogenic factors and Activin A independent of each other. Therefore, inhibition of the anti-angiogenic factors alone may not be a sufficient therapeutic strategy for preeclampsia.