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

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

doi:10.4049/jimmunol.1004026

Cited by 79 publications

(55 citation statements)

References 78 publications

(91 reference statements)

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“…In uterus and placenta, murine IL-10 is expressed in abundance and is necessary in protecting pregnancy from an inflammatory challenge [22]. Increased TNF-α/IL-6 signaling in mice is a key mechanism underlying increased preeclampsia and IL-6 blockade inhibited preeclamptic features in autoantibody-injected pregnant mice [23]. Our study shows that trigonelline suppresses the raised contents of IL-6 and TNF-α and promotes the lowered IL-10 content in placenta of diabetic pregnant mice.…”

Section: Discussionmentioning

confidence: 99%

Trigonelline Inhibits Inflammation and Protects β Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes

Zhou

Du²,

Zuo³

et al. 2017

Pharmacology

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Background: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. Methods: Diabetes was induced in female mice by intraperitoneal injection for continuous 5-day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). Results: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased β-cell replication and the decreased β-cell mass, and decreased the β-cell apoptosis of diabetic pregnant mice. Conclusion: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing β-cell mass, replication, and decreasing β-cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

Trigonelline Inhibits Inflammation and Protects β Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes

Zhou

Du²,

Zuo³

et al. 2017

Pharmacology

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“…Adoptive transfer of CD4ϩ T cells from RUPP rats induces hypertension, AT 1 -AA, inflammatory cytokines and sFlt-1, and endothelin-1 (ET-1) in normal pregnant rats, indicating the significant role these cells play in the pathogenesis of this disease (63). Furthermore, AT 1 -AA and sFlt-1 play a significant role in the development of endothelial dysfunction and hypertension in PE and have been found to correlate with PE severity in patients (15,25,30,43,60,64,65,67,69,71,72). AT 1 -AA infusion induces many pathophysiological characteristics of PE, including increased blood pressure, vascular resistance, ET-1, and sFlt-1 (8, 35).…”

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confidence: 99%

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Faulkner

Cornelius

Amaral

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14 -18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 Ϯ 2 mmHg compared with 102 Ϯ 3 mmHg in NP and decreased to 113 Ϯ 3 mmHg with VD2 and 115 Ϯ 3 mmHg with VD3 in RUPP rats. Circulating CD4ϩ T cells increased in RUPP to 7.90 Ϯ 1.36% lymphocytes compared with 2.04 Ϯ 0.67% in NP but was lowered to 0.90 Ϯ 0.19% with VD2 and 4.26 Ϯ 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 Ϯ 0.4 bpm in RUPPs to 8.3 Ϯ 0.5 bpm with VD2 and to 15.4 Ϯ 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 Ϯ 2.1-fold change from NP) and decreased with both VD2 (3.3 Ϯ 1.1-fold) and VD3 (3.1 Ϯ 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 Ϯ 6.6 pg/ml in VD2-treated and 91.0 Ϯ 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 Ϯ 19.9 pg/ml in RUPP rats. VD treatment reduced CD4ϩ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia. hypertension; immune activation; preeclampsia; vitamin D PREECLAMPSIA (PE) IS A CLINICAL condition occurring in up to 7% of pregnancies in the United States commonly manifesting in late gestation (Ͼ20 wk gestation) with hypertension, placental ischemia, and low birth weight (5,27,47,48,58). Current treatment strategies for preeclampsia are targeted at safely lowering blood pressure and alleviating maternal complications (5, 48). PE pregnancies are characterized by an abnormal immune profile compared with that seen in normal pregnancies. PE women exhibit an altered immune balance favoring proinflammatory factors, such as CD4ϩ T cells, B cells, inflammatory cytokines, and autoantibodies to the angiotensin type 1 receptor (AT 1 -AA), which are known to stimulate production of antiangiogenic protein-soluble FMS-like tyrosine kinase-1 (sFlt-1) (18,33,34,56,57). In contrast, anti-inflammatory T regulatory cells (TREGs) are decreased in PE (22,53,56). These immune alterations are recapitulated in the established experimental model of PE, the reduced uterine perfusion pressure (RUPP) rat (1,20,21). Adoptive transfer of CD4ϩ T cells from RUPP rats induces hypertension, AT 1 -AA, inflammatory cytokines and sFlt-1, and endothelin-1 (ET-1) in normal pregnant rats, indicating the significant role these cells play in the pathogenesis of this disease (63). Furthermore, AT 1 -AA and sFlt-1 play a significant role in the development of endothelial dysfunction and hyp...

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“…40 Also, when stimulating pregnant mice with serum from patients with preeclampsia, Zhou et al observed an increase in placental sFlt-1 expression that was blocked by pretreatment of the animals with an IL-6 neutralizing antibody. 25 This suggests a regulatory function of IL-6 in sFlt-1 production. In our study, we however saw no effect of IL-6 depletion on the production of sFlt-1 under low oxygen conditions.…”

Section: Discussionmentioning

confidence: 99%

“…24 Whether other cytokines are involved in the regulation of sFtl-1 production under hypoxic conditions in vivo has not been investigated so far. However, it is known that IL-6 inactivation in mice inhibits placental Flt-1 production induced by injection of human preeclamptic serum, 25 indicating a regulatory function of this cytokine on the placental sFlt-1 release.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Mediated Soluble Fms-Like Tyrosine Kinase 1 Increase Is Not Attenuated in Interleukin 6-Deficient Mice

et al. 2015

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The soluble fms-like tyrosine kinase 1 (sFlt-1), known to be increased in the serum of preeclamptic patients, is a relevant factor in causing maternal symptoms like hypertension and proteinuria. In this study, we aimed to reveal whether hypoxia is a cause of increased sFlt-1 levels and inflammation markers in vivo and whether these symptoms can be attenuated by interleukin 6 (IL-6) depletion. For this purpose, pregnant wild-type (wt) mice or IL-6 À/À mice on embryonic day 16 were placed under either normoxic (20.9% oxygen) or hypoxic (6% oxygen) conditions for 6 hours. This led to a rise of sFlt-1 levels in maternal serum, independent of the IL-6 status of the dam. Increased maternal sFlt-1 serum levels were, however, not due to an increase in sFlt-1 messenger RNA levels in the placenta. Moreover, there was no increase in inflammatory markers in neither wt mice nor IL-6 À/À mice. This suggests that hypoxia alone does not contribute to the induction of an inflammatory placenta. Also, the hypoxia-induced rise in sFlt-1 levels seems not to be mediated by IL-6 in vivo.

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

Cited by 79 publications

References 78 publications

Trigonelline Inhibits Inflammation and Protects β Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes

Trigonelline Inhibits Inflammation and Protects β Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Hypoxia-Mediated Soluble Fms-Like Tyrosine Kinase 1 Increase Is Not Attenuated in Interleukin 6-Deficient Mice

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