The NR4A receptors Nurr1 and Nur77 are increased in human placenta from women with gestational diabetes

• The NR4A proteins Nurr1, Nur77 and NOR1 are localised to the syncytiotrophoblast layer of placenta.
• Nurr1 and Nur77, but not NOR1, are increased in human placenta from women with gestational diabetes.
• TNF-α and IL-β increase the expression of Nurr1 and Nur77 in human primary trophoblast cells.
• Knockdown of Nurr1 decreased TNF-α induced cytokine expression from primary trophoblast cells.
• Knockdown of Nur77 decreased TNF-α induced cytokine expression from primary trophoblast cells.

IntroductionMembers of the NR4A subfamily are involved in a wide range of diseases including obesity and diabetes. The aim of this study was to determine the effect of maternal obesity and gestational diabetes mellitus (GDM) on the expression of the NR4A receptors Nurr1, Nur77 and NOR1.MethodsHuman placenta was obtained at the time of term Caesarean section from (i) lean and obese and normal glucose tolerant (NGT) pregnant women; and (ii) women with GDM and BMI-matched NGT women (n = 16 patients). Primary trophoblast cells, isolated from human term placenta, were used to determine the effect of pro-inflammatory cytokines on NR4A protein expression. Primary trophoblast cells were also used to assess the effect of Nurr1, Nur77 and NOR1 siRNA knockdown on pro-inflammatory cytokines.ResultsThere was no effect of pre-existing maternal obesity on Nurr1, Nur77 or NOR1 expression. Nurr1 and Nur77 expression were significantly higher in GDM placenta compared to NGT placenta, and in the presence of the pro-inflammatory cytokines TNF-α and IL-β in primary trophoblast cells. Knockdown of Nurr1 and Nur77 in human primary trophoblast cells significantly decreased TNF-α induced expression and secretion of IL-6 and IL-8.DiscussionNurr1 and Nur77, which were increased in human placenta from women with GDM, are involved in TNF-α induced-expression of pro-inflammatory cytokines. Pro-inflammatory cytokines are known to play a role in placental nutrient transport. Thus, the regulation of pro-inflammatory cytokines by Nurr1 and Nur77 suggest that these proteins may play a role in placental function and transport mechanisms.