A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice.
Hypoxia has been implicated in the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy. However, in vivo evidence and mechanistic understanding remain elusive. Preeclampsia is associated with impaired placental angiogenesis. We have recently shown that interleukin (IL)-10 can support trophoblast-driven endovascular crosstalk. Accordingly, we hypothesize that pathological levels of oxygen coupled with IL-10 deficiency induce severe preeclampsia-like features coupled with elevated production of antiangiogenic factors, apoptotic pathways, and placental injury. Exposure of pregnant wild-type and IL-10(-/-) mice to 9.5% oxygen resulted in graded placental injury and systemic symptoms of renal pathology, proteinuria (wild-type 645.15 ± 115.73 versus 198.09 ± 93.45; IL-10(-/-) 819.31 ± 127.85 versus 221.45 ± 82.73 μg/mg/24 hours) and hypertension (wild-type 118.37 ± 14.45 versus 78.67 ± 14.07; IL-10(-/-) 136.03 ± 22.59 versus 83.97 ± 18.25 mm Hg). Recombinant IL-10 reversed hypoxia-induced features in pregnant IL-10(-/-) mice confirming the protective role of IL-10 in preeclampsia. Hypoxic exposure caused marked elevation of soluble fms-like tyrosine kinase 1 (110.8 ± 20.1 versus 44.7 ± 11.9 ng/mL) in IL-10(-/-) mice compared with their wild-type counterparts (81.6 ± 13.1 versus 41.2 ± 8.9 ng/mL), whereas soluble endoglin was induced to similar levels in both strains (approximately 380 ± 50 versus 180 ± 31 ng/mL). Hypoxia-induced elevation of p53 was associated with marked induction of proapoptotic protein Bax, downregulation of Bcl-2, and trophoblast-specific apoptosis in utero-placental tissue. Collectively, we conclude that severe preeclampsia pathology could be triggered under certain threshold oxygen levels coupled with intrinsic IL-10 deficiency, which lead to excessive activation of antiangiogenic and apoptotic pathways.
Department of Pediatrics, Women and Infants Hospital–Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.
Zhongbin
Z
Lai
Satyan
S
Kalkunte
Surendra
S
Sharma
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000378:metabolism / Q000503:physiopathology*; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D014327:Trophoblasts / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D016753:Interleukin-10; D040281:Vascular Endothelial Growth Factor Receptor-1
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