A Critical Role of Interleukin-10 in Modulating Hypoxia-Induced Preeclampsia-Like Disease in Mice

Abstract

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 cross-talk. Accordingly, we hypothesize that pathologic levels of oxygen coupled with IL-10 deficiency induce severe preeclampsia-like features coupled with elevated production of anti-angiogenic 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, proteinurea (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 mmHg). 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 to their wild type counterparts (81.6±13.1 versus 41.2±8.9 ng/ml), whereas soluble endoglin was induced to the similar levels in both strains (~380±50 versus 180±31 ng/ml). Hypoxia-induced elevation of p53 was associated with marked induction of pro-apoptotic protein Bax, down-regulation 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 anti-angiogenic and apoptotic pathways.

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

“…Whereas the presence of activated neutrophils in the maternal circulation has been reported to be detrimental in pregnancy complications, including preeclampsia (22,48), our observations suggest that a regulatory nonactivated proapoptotic neutrophil phenotype promoted by pregnancy hormones might be essential for normal placentation, including its vascular development. The cytokine milieu that results from niT-cell generation could favor the establishment of a proangiogeneic environment, with both IL-10 and IL-17 promoting vessel development (21,49) and IL-17 promoting trophoblast invasion (27,50), both key processes in spiral artery remodelling (26). In addition, and more specifically, we have shown that niT cells make IL-17-dependent VEGF, lending further support to their proangiogenic function within the placenta.…”

Interleukin 10 Deficiency Exacerbates Toll-Like Receptor 3–Induced Preeclampsia-Like Symptoms in Mice

“…We have also treated human cytotrophoblasts with poly I:C for 12, 24, and 48 hours and did not see any changes in BAX and caspase 3 expression (data not shown). Lai et al 46 also reported that hypoxic, pregnant IL-10 KO mice developed atrophic tubules, interstitial edema, and enlarged glomeruli. However, kidneys from P and P-PIC WT and IL-10 KO mice did not exhibit any tubular atrophy or interstitial or glomerular changes (data not shown).…”

“…However, in pregnant IL-10 KO mice, systolic blood pressure failed to decrease and was significantly increased at day 18 of gestation compared with pregnant WT mice. Lai et al 46 reported that pregnant IL-10 KO mice exposed to hypoxia early in pregnancy not only exhibited PE-like symptoms but increased placental expression of the proapoptotic molecules BAX and caspase 3. However, we found that both P and P-PIC IL-10 KO mice had increased placental BAX expression compared with WT mice, whereas P IL-10 KO mice had the most placental caspase 3 expression ( Figure S5).…”

Association of interleukin-10 gene promoter polymorphisms with recurrent pregnancy loss: a meta-analysis

“…Furthermore, increased IL-10 expression is associated with successful reproduction and IL-10 deficiency is associated with many adverse pregnancy outcomes such as PRL, preterm birth, and preeclampsia [11,[42][43][44]. Animal experimental studies also show that administration of recombinant IL-10 reverses or alleviates symptoms of many adverse pregnancy outcomes [45][46][47][48]. Polymorphic change in the human IL-10 gene promoter are thought to contribute to reduced IL-10 production and to the onset and severity of autoimmune, neoplastic, and infectious disorders such as systemic lupus erythematosus and Alzheimer's disease [49][50][51].…”