Expression Of Nuclear Factor KappaB In Placenta Tissues Of Patients With Intrahepatic Cholestasis Of Pregnancy And Its Significance

Objective: Intrahepatic cholestasis of pregnancy (ICP) is a disease predominantly of the third trimester of pregnancy, characterized primarily by pruritus, biochemical disturbances in liver enzymes, and less frequently jaundice. Although maternal pruritus can be severe, overall maternal morbidity and mortality associated with ICP is low. However, fetal morbidity and mortality are significant with associated risks for meconium-stained amniotic fluid, acute onset of fetal compromise, spontaneous preterm labor, and intrauterine fetal demise. Its etiology and pathogenesis are still unclear. Recently, study on immunological changes has been emphasized in patients with ICP.In this study, the relationship between nuclear factor kappaB (NF-κB) and cyclooxygenase-2 (cox-2), tumor necrosis factor-alpha (TNF-α),interleukin-6(IL-6),estrogen(E2), progestin(P) were investigated by comparison of their changes in ICP and normal placenta,to evaluate the roles of NF-kB in the etiology and pathogenesis of ICP. Methods: The expressions of NF-κB and COX-2 in placenta of patients with normal pregnancy and ICP were determined by immunohistochemistry combined tissue microarray. The placetas of normal pregnancy(n=5) and ICP(n=5) after 4h of incubation with ICP serum in the absence or presence of dexamethasone(DEX) and SASP also were detected for NF-κB and COX-2 expression by immunohistochemistry, at the same time the concentrations of TNF-αand IL-6 in supernatant were quantified by ELISA and the release of E2 and P were measured by radioimmunology. Results: The levels of NF-κB and COX-2 in ICP placenta were higher than those in normal placenta and were related to the severity of ICP.There was significant correlation between NF-κB and COX-2.Both of them were significantly increased after treatment of ICP serum.In vitro,the release of TNF-αand IL-6 in ICP placenta were higher than those in normal placenta after 4h culture. The NF-κB expression was positively correlated with the levels of TNF-αand TNF-α/IL-6 in normal placentas after treatment by ICP serum.The secretion of TNF-αwas inhibited by SASP, a kind of NF-κB atagonists,and dexamethasone can reverse the increasing of TNF-αstimulated by ICP serum.The levels of E2 were no significant difference between two placenta type groups while the levels of P in ICP placenta were higher than those in normal placenta. Tissue microarray has certain advantages in placental pathological research. Conclusion: NF-κB is activated in the pathogenesis of ICP.It is concerned with preterm labor in ICP by regulating the synthesis and release of COX-2. It also participates in the immune malfunction of ICP through regulating the balance of Th1/Th2 factors and has an important role in pathophysiology of ICP.However, NF-κB pathways is not the major factor in the regulation of E2 and P secretion in placenta.