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Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBP?-mediated transcriptional suppression.

ABSTRACT: Activation of the unfolded protein response (UPR) by endoplasmic reticulum (ER) stress culminates in extensive gene regulation, with transcriptional upregulation of genes that improve the protein folding capacity of the organelle. However, a substantial number of genes are downregulated by ER stress, and the mechanisms that lead to this downregulation and its consequences on cellular function are poorly understood. We found that ER stress led to coordinated transcriptional suppression of diverse cellular processes, including those involved in cytokine signaling. Using expression of the IL-4/IL-13 receptor subunit Il4ra as a sentinel, we sought to understand the mechanism behind this suppression and its impact on inflammatory signaling. We found that reinitiation of global protein synthesis by GADD34-mediated dephosphorylation of eIF2? resulted in preferential expression of the inhibitory LIP isoform of the transcription factor C/EBP?. This regulation was in turn required for the suppression of Il4ra and related inflammatory genes. Suppression of Il4ra was lost in Cebpb(-/-) cells but could be induced by LIP overexpression. As a consequence of Il4ra suppression, ER stress impaired IL-4/IL-13 signaling. Strikingly, Cebpb(-/-) cells lacking Il4ra downregulation were protected from this signaling impairment. This work identifies a novel role for C/EBP? in regulating transcriptional suppression and inflammatory signaling during ER stress.

SUBMITTER: Arensdorf AM

PROVIDER: S-EPMC3757336 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression.

Arensdorf Angela M AM Rutkowski D Thomas DT

Journal of cell science 20130626 Pt 17

Activation of the unfolded protein response (UPR) by endoplasmic reticulum (ER) stress culminates in extensive gene regulation, with transcriptional upregulation of genes that improve the protein folding capacity of the organelle. However, a substantial number of genes are downregulated by ER stress, and the mechanisms that lead to this downregulation and its consequences on cellular function are poorly understood. We found that ER stress led to coordinated transcriptional suppression of diverse ...[more]

PMID: 23813955

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Project description:Cyfluthrin, a typical type II pyrethroid pesticide, is widely used in house hygiene and agricultural pest control. Several epidemiological investigations have found that maternal pyrethroid exposure is connected to adverse pregnancy outcomes. However, the underlying mechanisms remain to be elucidated. Thus, we evaluated the effect of cyfluthrin exposure during pregnancy on placenta development in vivo. In the current study, Pregnant SD rats were randomly divided into four groups and administered 6.25, 12.5, and 25 mg/kg body weight cyfluthrin or an equivalent volume of corn oil by gavage from GD0 to GD19. The results have shown that gestational exposure to cyfluthrin exerted no effect on the fetal birth defect, survival to PND4, or fetal resorption and death. However, live fetuses and implantation sites significantly decreased in the high-dose cyfluthrin-treated group. Moreover, a significant reduction in placenta weight and diameter was observed in rats. Correspondingly, the fetal weight and crown-rump length from dams exposed to cyfluthrin were reduced. Cyfluthrin-treat groups, the total area of the placenta, spongiotrophoblast area, and labyrinth area had abnormal changes. Meanwhile, the area of blood sinusoid and CD34-positive blood vessel numbers in the placenta were considerably reduced, as well as abnormal expression of placental pro-angiogenic and anti-angiogenic factors in dams exposed to cyfluthrin. Further observation by transmission electron microscopy revealed significant changes in the ultrastructure of the medium-dose and high-dose groups. Additional experiments showed gestational exposure to cyfluthrin inhibited proliferation and induced apoptosis of placentas, as decreased PCNA-positive cells and increased TUNEL-positive cells. Furthermore, western blot and qPCR analysis revealed that gestational exposure to medium-dose and high-dose cyfluthrin increased the expression of GRP78, and three downstream mRNA and proteins (p-eIF2α, ATF4, and CHOP) of the PERK signaling, indicating that endoplasmic reticulum (ER) stress-mediated PERK/eIF2α/ATF4/CHOP signaling pathway in rat placentas was activated. Our study demonstrated that gestational exposure to cyfluthrin leads to placental developmental disorder, which might be associated with ER stress-mediated PERK signaling pathway.

Dataset Information

Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBP?-mediated transcriptional suppression.

Publications

Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression.

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