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Am J Physiol Cell Physiol 297: C1228-C1235, 2009. First published September 9, 2009; doi:10.1152/ajpcell.00195.2009
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Membrane Transporters, Ion Channels, and Pumps

IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2

H. N. Jones, T. Jansson, and T. L. Powell

Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, Cincinnati, Ohio

Submitted 4 May 2009 ; accepted in final form 22 June 2009

Changes in placental nutrient transport are closely associated with abnormal fetal growth. However, the molecular mechanisms underlying the regulation of placental amino acid transporters are unknown. We demonstrate that physiological concentrations of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-{alpha} stimulate the activity of amino acid transporter system A, but not system L, in cultured human primary trophoblast cells. Both cytokines increased the gene and protein expression of the Na+-coupled neutral amino acid transporter (SNAT)2 isoform and upregulated SNAT1 protein expression. IL-6 increased Tyr705 phosphorylation of signal transducer and activator of transcription 3 (STAT3). In cells transfected with small interfering RNA (siRNA) targeting STAT3, the RNA and protein expression of SNAT2, but not SNAT1, was reduced and the stimulating effect of IL-6 on system A activity was abolished. Despite eliciting similar responses in amino acid transport activity and transporter expression, TNF-{alpha} effects on system A activity were not mediated through the JAK/STAT pathway. In conclusion, we have identified a novel regulatory pathway involving increased gene expression of the SNAT2 isoform mediated by a STAT-dependent pathway, which links IL-6 to increased activity of system A, a ubiquitously expressed transporter of neutral amino acids. From these new findings, we propose that upregulation of amino acid transporters by cytokines may contribute to increased placental nutrient transport and fetal overgrowth, which are commonly found in pregnancies complicated by maternal diabetes and obesity.

placenta; pregnancy; cytokines; obesity


Address for reprint requests and other correspondence: H. N. Jones, The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229 (e-mail: helen.jones{at}cchmc.org).






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