Dataset Information

Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia.

ABSTRACT: Increased inflammatory response plays a significant role in the vascular pathophysiology in preeclampsia. However, the mechanism for increased inflammatory response in preeclampsia is largely unknown. Interleukin (IL)-6 levels are elevated in women with preeclampsia. IL-6 and its receptors, IL-6R and glycoprotein (gp)130, play a critical role in mediating antiinflammatory response via induction of SOCS-3 (suppressor of cytokine signaling-3). However, IL-6 receptor levels and expressions have not been studied in preeclampsia. In this study, we measured IL-6 and its 2 soluble receptors, soluble IL-6R and soluble gp130, in maternal plasma from normal and preeclamptic pregnant women and found that not only IL-6 but also soluble gp130 levels were significantly higher in preeclamptic women than in normotensive pregnant controls. We further examined IL-6R, gp130, and SOCS-3 expressions in maternal vessels and leukocytes and found that gp130 and SOCS-3 expressions were downregulated in both vessel endothelium and leukocytes from preeclampsia. Different patterns for IL-6R and gp130 expressions were found. IL-6R expression was also downregulated in leukocytes from preeclampsia. Our results suggest that increased plasma soluble gp130/soluble IL-6R/IL-6 ratio and reduced membrane transsignaling gp130 expression could contribute to decreased SOCS-3 expression and subsequent reduction in SOCS-3 antiinflammatory activity in women with preeclampsia. Thus, reduced gp130 and SOCS-3 expressions may offer, at least in part, a plausible explanation of reduced antiinflammatory protection in the maternal vascular system in preeclampsia.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3062273 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia.

Wang Yuping Y Lewis David F DF Gu Yang Y Zhao Shuang S Groome Lynn J LJ

Hypertension (Dallas, Tex. : 1979) 20101220 2

Increased inflammatory response plays a significant role in the vascular pathophysiology in preeclampsia. However, the mechanism for increased inflammatory response in preeclampsia is largely unknown. Interleukin (IL)-6 levels are elevated in women with preeclampsia. IL-6 and its receptors, IL-6R and glycoprotein (gp)130, play a critical role in mediating antiinflammatory response via induction of SOCS-3 (suppressor of cytokine signaling-3). However, IL-6 receptor levels and expressions have not ...[more]

PMID: 21173340

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Project description:Excessive accumulation of misfolded proteins was recently demonstrated in preeclampsia. We examined levels and activity of circulatory proteasome and immunoproteasome (inflammatory subtype) in preeclampsia and hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome. We analyzed samples from women with hypertensive pregnancy disorders (n=115), including preeclampsia with severe features (sPE) and HELLP syndrome, and normotensive controls (n=45). Plasma proteasome and immunoproteasome immunoreactivity were determined by quantifying the α-subunit of the 20S core and β5i (proteasome subunit beta 8 [PSMB8]), respectively. Plasma proteasome activity was analyzed with fluorogenic substrates. MG132, lactacystin, and ONX0914 were used to inhibit the circulating proteasome and immunoproteasome, respectively. Plasma cytokine profiles were evaluated by multiplex immunoassay. Placental expression of β5 (constitutive proteasome) and β5i (immunoproteasome) was interrogated by immunohistochemistry. Women with sPE had increased plasma 20S levels ( P<0.001) and elevated lytic activities (chymotrypsin-like 7-fold, caspase-like 4.2-fold, trypsin-like 2.2-fold; P <0.001 for all) compared with pregnant controls. Women with features of HELLP displayed the highest plasma proteasome levels and activity, which correlated with decreased IFN-γ (interferon-γ), and increased IL (interleukin)-8 and IL-10. In sPE and HELLP, chymotrypsin-like activity was suppressed by proteasome inhibitors including ONX0914. Compared with gestational age-matched controls, sPE placentas harbored increased β5 and β5i immunostaining in trophoblasts. β5i signal was elevated in HELLP with predominant staining in villous core, extravillous trophoblasts in placental islands, and extracellular vesicles in intervillous spaces. Pregnancy represents a state of increased proteostatic stress. sPE and HELLP were characterized by significant upregulation in circulating levels and lytic activity of the proteasome that was partially explained by placental immunoproteasome upregulation.

Project description:ObjectivesSuppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling that function via the JAK/STAT pathway (Janus kinase/signal transducers and activators of transcription). Eight SOCS proteins, SOCS1-SOCS7 and CIS-1 (cytokine-inducible SH2-domain, with similar structure to the other SOCS proteins) have been identified, of which SOCS1, 2, and 3 and CIS-1 are the best characterised. A characteristic feature of osteoarthritis (OA) is increased production by articular chondrocytes of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα), which may be induced by mechanotransduction and contribute to cartilage destruction. In this study, we have compared the gene expression of SOCS1, 2, 3 and CIS-1 in healthy and OA human chondrocytes, and also analyzed the effects of IL-1β and TNFα on the levels of mRNA encoding these SOCS family members. In addition, SOCS2 protein production was assessed and the CpG methylation status of the SOCS2 promoter was analyzed to determine the role of epigenetics in its regulation.MethodsFemoral heads were obtained after joint replacement surgery for late stage OA and hemiarthroplasty following a fracture of the neck of femur (#NOF). Chondrocytes from the superficial layer of OA cartilage and the deep zone of #NOF cartilage were isolated by sequential treatment with trypsin, hyaluronidase and collagenase B. Total DNA and RNA were extracted from the same chondrocytes, and the levels of SOCS1, 2, 3 and CIS-1 mRNA were determined by qRT-PCR. The percentage of methylation in the CpG sites of the SOCS2 proximal promoter was quantified by pyrosequencing. Alternatively, healthy chondrocytes were isolated from #NOF cartilage and cultured with and without a mixture of IL-1β and oncostatin M (OSM, both 2.5ng/ml) or TNFα (10ng/ml). The short-term cultures with single cytokine treatment were harvested 24 and 72h after treatment, and the long-term cultures were maintained for 4-5 weeks until confluent with periodical cytokine stimulation. Total RNA was extracted and mRNA levels were determined by qRT-PCR.ResultsThe SOCS2 and CIS-1 mRNA levels were reduced by approximately 10-fold in OA samples compared to control samples, while SOCS1 and SOCS3 showed similar expression patterns in OA and control chondrocytes. The SOCS2 and CIS-1 mRNA levels declined by 6-fold and 3-fold with long-term treatment with IL-1β and OSM in combination and TNFα, respectively. There was no significant difference in the CpG methylation status of the SOCS2 promoter between healthy and OA chondrocytes. Similarly, cytokine stimulation did not change the CpG methylation status of the SOCS2 promoter.ConclusionsThis study demonstrates the reduced expression of SOCS2 and CIS-1 in OA, while SOCS1 and SOCS3 were unaffected. The observation that long-term treatment with inflammatory cytokines attenuated the expression of SOCS2 and CIS-1 suggests a potential positive feedback mechanism, and a role of SOCS in the pathology of OA.

Dataset Information

Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia.

Publications

Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia.

Similar Datasets

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