Autoantibody-Mediated IL-6-Dependent Endothelin-1 Elevation Underlies Pathogenesis in a Mouse Model of Preeclampsia

作者：Zhou, Cissy Chenyi; Irani, Roxanna A.; Dai, Yingbo; Blackwell, Sean C.; Hicks, M. John; Ramin, Susan M.; Kellems, Rodney E.; Xia, Yang^*

来源：The Journal of Immunology, 2011, 186(10): 6024-6034.

DOI：10.4049/jimmunol.1004026

• TUMOR-NECROSIS-FACTOR
• RECEPTOR AGONISTIC ANTIBODIES
• RENIN-ANGIOTENSIN SYSTEM
• FACTOR-ALPHA
• UTERINE PERFUSION
• AT(1) RECEPTOR
• PREGNANT RATS
• SUPEROXIDE-DISMUTASE
• INCREASED EXPRESSION
• ANGIOGENIC FACTORS

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. Elevated circulating endothelin-1 (ET-1) is associated with the disease. However the molecular basis of increased ET-1 production and its role in PE are unknown. This study aimed to investigate the causative factors, pathological role of elevated ET-1 production in PE, and the underlying mechanisms. In this study, we found that IgG from women with PE, in contrast to IgG from normotensive pregnant women, induced preproET-1 mRNA expression via angiotensin II type 1 receptor activation in kidneys and placentas in pregnant mice. The ET-A receptor-specific antagonist BQ123 significantly attenuated autoantibody-induced hypertension, proteinuria, and renal damage in pregnant mice, demonstrating that autoantibody-induced ET-1 production contributes to pathophysiology. Mechanistically, we discovered that IL-6 functioned downstream of TNF-alpha signaling, contributing to increased ET-1 production in pregnant mice. IL-6 blockade inhibited preeclamptic features in autoantibody-injected pregnant mice. Extending the data to human studies, we found that IL-6 was a key cytokine underlying ET-1 induction mediated by IgG from women with PE in human placental villous explants and that endothelial cells are a key source of ET-1. Overall, we provide human and mouse studies showing that angiotensin II type I receptor-agonistic autoantibody is a novel causative factor responsible for elevated ET-1 production and that increased TNF-alpha/IL-6 signaling is a key mechanism underlying increased ET-1 production and subsequent maternal features. Significantly, our findings revealed novel factors and signaling cascades involved in ET-1 production, subsequent disease symptom development, and possible therapeutic intervention in the management of PE. The Journal of Immunology, 2011, 186: 6024-6034.

• 出版日期2011-5-15