title: Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.
abstract: Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10pg/ml) for 24h. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth.
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Electronic address: aye@uthscsa.edu.
authors.forename: Irving L M H
authors.initials: IL
authors.lastname: Aye
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Powell
mesh_terms: D026924:Amino Acid Transport System A / Q000378:metabolism*; D027062:Amino Acid Transport System L / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D053858:Metabolic Networks and Pathways; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D026924:Amino Acid Transport System A; D027062:Amino Acid Transport System L; D000596:Amino Acids; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Inflammation; Insulin-resistance; Maternal–fetal exchange; Placenta
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