title: Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity.
abstract: Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine (IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling.
authors: Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA.
authors: Jessica
authors: J
authors: Saben
authors: Ying
authors: Y
authors: Zhong
authors: Horacio
authors: H
authors: Gomez-Acevedo
authors: Keshari M
authors: KM
authors: Thakali
authors: Sarah J
authors: SJ
authors: Borengasser
authors: Aline
authors: A
authors: Andres
authors: Kartik
authors: K
authors: Shankar
mesh_terms: D051700:Activating Transcription Factor 3 / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D009765:Obesity / Q000276:immunology*; D010168:Palmitates / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000276:immunology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology*; D026362:Serum Response Factor / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D015850:Interleukin-6; D016209:Interleukin-8; D010168:Palmitates; D026362:Serum Response Factor; D014409:Tumor Necrosis Factor-alpha
keywords: developmental programming; early growth response protein-1; fatty acids; gestational obesity; mitogen-activated protein kinase
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