IL-6-induced pathophysiology during pre-eclampsia: potential therapeutic role for magnesium sulfate?

Abstract

Pre-eclampsia is defined as new onset hypertension with proteinuria during pregnancy. Pre-eclampsia is also characterized by endothelial cell activation and dysfunction and intrauterine growth restriction. Preeclamptic women display a chronic inflammatory response characterized by elevated inflammatory cytokines, circulating monocytes, neutrophils, and T and B lymphocytes secreting autoantibodies that activate the angiotensin II type I receptor (AT1-AA). Although the pathophysiology of pre-eclampsia is becoming more defined, the genesis of the disease is still largely unknown. Furthermore, the only treatment for extreme forms of the disease is bed rest and administration of magnesium sulfate to sustain the pregnancy a few days prior to early delivery of the fetus, which can lead to devastating neurological and physical effects for the newborn. Administration of magnesium sulfate is routinely given without adverse effects. The focus of this review is to discuss the cascade of events leading to cytokines, specifically interleukin-6 (IL-6), in stimulating vasoactive substances such as AT1-AA (Figure 1) and to examine the mechanism whereby administration of magnesium sulfate can be beneficial during pre-eclampsia. One area is to decrease vascular resistance index parameters determined by Doppler velocimetry. Another potential area of benefit with magnesium sulfate administration may be to decrease inflammatory responses or decrease cardiovascular mechanisms stimulated by overexpression of inflammatory cytokines in response to placental ischemia or animal models of elevated IL-6 during pregnancy. Further studies identifying IL-6-driven mechanisms playing a role in the development of hypertension during pregnancy and how administration of magnesium sulfate can suppress them are critical to improve decisions affecting patient care in women with pre-eclampsia. The results of these types of studies will be advantageous to further our knowledge of the pathophysiological ramifications associated with pre-eclampsia and to further therapeutic development for this disease.

Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response

“…31,32 Hence, our findings that hypoxic treatment of the dual placental perfusion system produces significantly higher levels of TNF-a and IFN-g closely parallel the in vivo response in preeclampsia. Furthermore, both IL-6 and IL-8 are found to be significantly increased in preeclampsia, 33,34 and both these pro-inflammatory cytokines were also secreted at a significantly increased rate under hypoxic treatment of the dual placental perfusion system compared with the normoxic group. As there are very few maternal lymphatic cells present in this system, this response to hypoxia most likely originates from the placental trophoblast.…”

Evaluation of Inflammatory Markers in Pregnant Women at Risk, for the Prediction of Preeclampsia

“…Th e study investigated the serum values of hs-CRP and IL-6 in the fi rst trimester of pregnancy (weeks [10][11][12][13][14] and in the second trimester of pregnancy (weeks [20][21][22][23][24]. Th e samples were analyzed according to the following study protocol: 3 ml blood were collected on anticoagulant, the plasma was separated by centrifugation for 15 min at 1000 xg.…”

“…IL-6 is a multifunctional proinfl ammatory cytokine, produced by vascular endothelial cells, the placenta and leukocytes, with a decisive role in infl ammatory response and the control of T cell diff erentiation in adaptive immunity. IL-6 is also involved in trophoblast proli-feration and invasion and in oxidative stress, being the key circulating marker of endothelial dysfunction [10][11][12].…”

Hypertension in response to CD4+ T cells from reduced uterine perfusion pregnant rats is associated with activation of the endothelin-1 system

“…In recent years, much obstetric research has focused on identifying components of the immune system that are activated and play a role in the pathophysiology of preeclampsia. We now know that preeclampsia is associated with elevated inflammatory cytokines, activation of T lymphocytes, and B lymphocyte secreting antibodies that activate receptors that are important in regulating sodium and water homeostasis, such as the angiotensin II type I receptor (9,14,15,26,29).Our laboratory recently reported that placental ischemia (RUPP) increases circulating CD4 ϩ T cells that secrete significantly more tumor necrosis factor-␣ (TNF-␣) and the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) compared with normal pregnant (NP) rats (29). In addition, adoptive transfer of CD4 ϩ T cells from RUPP rats into NP rats increased blood pressure and is associated with an increase in inflammatory cytokines, TNF-␣, interleukin-6, interleukin-17, and sFlt-1, similar to that seen with the RUPP model (29).…”

“…In recent years, much obstetric research has focused on identifying components of the immune system that are activated and play a role in the pathophysiology of preeclampsia. We now know that preeclampsia is associated with elevated inflammatory cytokines, activation of T lymphocytes, and B lymphocyte secreting antibodies that activate receptors that are important in regulating sodium and water homeostasis, such as the angiotensin II type I receptor (9,14,15,26,29).…”