IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2
Abstract
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)-α 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-α 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.
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System A and L activity can be modulated by pro-inflammatory cytokines, such as TNF-α and IL-6.
“These can also be modulated by pro-inflammatory cytokines, such as TNF-α and IL-6 [151].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [151]
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“In keeping with this, IL-6 stimulates trophoblast fatty acid accumulation [17] and increases trophoblast SystemA amino acid transporter activity and expression [14].”
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Short chain fatty acids as novel therapeutics for gestational diabetes.
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Liong, S., & Lappas, M. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.02.016 · Cited by 42 · see citing works
“For example, in trophoblast cells, IL-6 increases 452 fatty acid accumulation (Lager et al., 2011) and upregulates the expression of System A amino acid transporters (Jones et al., 2009).”
BackgroundAmino Acid Transporters in the Regulation of Human Skeletal Muscle Protein Metabolism
Dickinson, J., & Rasmussen, B. (2013) · Current opinion in clinical nutrition and metabolic care · doi:10.1097/mco.0b013e3283653ec5 · Cited by 42 · see citing works
“STAT3 has been shown to be associated with the upregulation of SNAT2 in response to inflammatory markers [47], indicating that the upregulation of amino acid transporters following resistance exercise in older adults could be mediated through a stress response to the exercise bout.”
BackgroundNing, H., Tao, H., Weng, Z., & Ζhao, X. (2016) · Acta Diabetologica · doi:10.1007/s00592-016-0867-8 · Cited by 41 · see citing works
“These changes in placental function may be caused by altered inflammatory profiles in the mother, placenta and fetus in obesity and GDM, leading to the comorbidities observed in these pregnancies [53, 54].”
BackgroundAye, I. L. M. H., Jansson, T., & Powell, T. L. (2015) · Physiological Reports · doi:10.14814/phy2.12594 · Cited by 44 · see citing works
“IL-6 and TNF-a have been previously shown to stimulate System A amino acid transporter activity in cultured primary human trophoblast cells (PHTs) of the term placenta (Jones et al. 2009) as well as in hepatocyte cell lines (Watkins et al.”
BackgroundResultInfluentialSelf-citationDifferential regulation of placental amino acid transport by saturated and unsaturated fatty acids
Lager, S., Jansson, T., & Powell, T. L. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00196.2014 · Cited by 42 · see citing works
“Furthermore, in our AJP-Cell Physiol • doi:10.1152/ajpcell.00196.2014 • www.ajpcell.org previous study (19), we showed that OA (400 M) activated JNK and STAT3 while having no effect on the mTOR pathway.”
BackgroundInfluentialSelf-citationRegulation of placental amino acid transport in health and disease
Shimada, H., Powell, T. L., & Jansson, T. (2024) · Acta Physiologica · doi:10.1111/apha.14157 · Cited by 42 · see citing works
“177,178 The regulation of SNAT2 and LAT1 membrane trafficking by mTORC1 and 2 is mediated by distinct mechanisms (Figure 3).”
BackgroundInfluentialSelf-citationMarkert, U., Morales-Prieto, D., & Fitzgerald, J. (2011) · Expert Review of Clinical Immunology · doi:10.1586/eci.11.60 · Cited by 36 · see citing works
Zhang, Y.-L., Duan, X., Jiang, W.-D., Feng, L., Wu, P., Liu, Y., Jiang, J., Kuang, S.-Y., Tang, L., Tang, W.-N., et al. (2019) · Fish Physiology & Biochemistry · doi:10.1007/s10695-019-00648-z · Cited by 34 · see citing works
Lager, S., Ramirez, V. I., Acosta, O. M., Meireles, C. L., Miller, E., Gaccioli, F., Rosario, F. J., Gelfond, J. A. L., Hakala, K. W., Weintraub, S. T., et al. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01384 · Cited by 39 · see citing works
“mTOR and STAT3 are known positive regulators of placental amino acid transport (20, 24, 25).”
Self-citationAraújo, J. R., Correia‐Branco, A., Moreira, L., Ramalho, C. M. A., Martel, F., & Keating, E. (2013) · Pediatric Research · doi:10.1038/pr.2013.14 · Cited by 26 · see citing works
“These findings support the idea advanced by others that leptin (19), and eventually TNF-α (36), may act as regulators of placental nutrient transport and therefore of fetal growth.”
Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction.
Borg, A., Yong, H., Lappas, M., Degrelle, S., Keogh, R., Costa, F. D. S., Fournier, T., Abumaree, M., Keelan, J., Kalionis, B., et al. (2015) · Reproduction · doi:10.1530/rep-14-0622 · Cited by 32 · see citing works
“STAT3 regulation on placental amino acid transport was demonstrated in chorionic villous explants (Jones et al. 2009, 2010).”
BackgroundGajera, D., Trivedi, V., Thaker, P., Rathod, M., & Dharamsi, A. T. (2023) · Hormone and Metabolic Research · doi:10.1055/a-2061-9441 · Cited by 36 · see citing works
“Excess protein consumption may potentially lead to GDM through altered amino acid transport [17].”
BackgroundMcColl, E. R., & Piquette‐Miller, M. (2019) · American Journal of Reproductive Immunology · doi:10.1111/aji.13115 · Cited by 34 · see citing works
Effects of Prenatal Nutrition and the Role of the Placenta in Health and Disease
Myatt, L., & Thornburg, K. L. R. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7614-0_2 · Cited by 36 · see citing works
Antiviral Inflammation during Early Pregnancy Reduces Placental and Fetal Growth Trajectories
Baines, K. J., Rampersaud, A. M., Hillier, D. M., Jeyarajah, M. J., Grafham, G. K., Eastabrook, G. D. M., Lacefield, J. C., & Renaud, S. J. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900888 · Cited by 25 · see citing works
Albeitawi, S., Bani-Mousa, S.-U., Jarrar, B., Aloqaily, I., Al-Shlool, N., Alsheyab, G., Kassab, A., Qawasmi, B., & Awaisheh, A. (2025) · Biomolecules · doi:10.3390/biom15030443 · Cited by 29 · see citing works
“IL-6 also stimulates system A amino acid transporter activity in primary trophoblasts, increasing the uptake of essential amino acids [163].”
Kowash, H. M., Potter, H. G., Woods, R. M., Ashton, N., Hager, R., Neill, J. C., & Glazier, J. D. (2022) · Clinical Science · doi:10.1042/cs20220245 · Cited by 23 · see citing works
Effects of maternal obesity on early and long-term outcomes for offspring
Reynolds, R. M., & Stirrat, L. (2014) · Research and Reports in Neonatology · doi:10.2147/rrn.s46783 · Cited by 21 · see citing works
“Furthermore, physiological concentrations of IL-6 and TNF-α have also been shown to stimulate the activity of amino acid transporter system A.(37) It has been suggested that in maternal obesity, the increased levels of IL-6 and TNF-α in the placenta could stimulate system A transporter activity further, thus increasin…”
BackgroundMolecular Principles of Intrauterine Growth Restriction in Plasmodium Falciparum Infection
Seitz, J., Prieto, D. M. M., Fávaro, R. R., Schneider, H., & Markert, U. R. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00098 · Cited by 29 · see citing works
“In vitro studies show that proinflammatory cytokines such as 1β, IL-6, and TNF lead to System A transporter dysregulation (123, 124).”
BackgroundChen, Y.-Y., Powell, T., & Jansson, T. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.12.009 · Cited by 21 · see citing works
“For example, our previous studies showed pro-inflammatory cytokines stimulated SNTA2 expression in cultured PHT cells (Aye et al., 2015; Jones et al., 2009).”
ResultSelf-citationSirtuins-Mediators of Maternal Obesity-Induced Complications in Offspring?
Nguyen, L. T., Chen, H., Pollock, C. A., & Saad, S. (2016) · The FASEB Journal · doi:10.1096/fj.15-280743 · Cited by 19 · see citing works
“Supporting this hypothesis, an in vivo study has demonstrated that sodiumcoupled neutral amino acid transporter (SNAT)1 and SNAT2 mRNA expression were up-regulated by increased IL-6 concentrations in culturedhumanprimary trophoblast cells (70).”
BackgroundLiong, S., & Lappas, M. (2017) · Placenta · doi:10.1016/j.placenta.2017.01.124 · Cited by 17 · see citing works
Jamilian, M., Samimi, M., Ebrahimi, F. A., Aghadavod, E., Mohammadbeigi, R., Rahimi, M., & Asemi, Z. (2017) · Biological Trace Element Research · doi:10.1007/s12011-017-1045-8 · Cited by 20 · see citing works
“regulating placental transport of nutrients including fatty acids [34] and amino acids [24].”
BackgroundAssociation of SLC38A4 and system A with abnormal fetal birth weight.
Li, Z., Lai, G., Deng, L.-J., Han, Y., Zheng, D., & Song, W.-W. (2012) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2011.392 · Cited by 18 · see citing works
Slit2 E xerts Anti‐Inflammatory Actions in Human Placenta and is Decreased with Maternal Obesity
Lim, R., & Lappas, M. (2014) · American Journal of Reproductive Immunology · doi:10.1111/aji.12334 · Cited by 15 · see citing works
l-Methionine Placental Uptake: Characterization and Modulation in Gestational Diabetes Mellitus
Araújo, J. R., Correia‐Branco, A., Ramalho, C. M. A., Gonçalves, P., Pinho, M. J., Keating, E., & Martel, F. (2013) · Reproductive Sciences · doi:10.1177/1933719113488442 · Cited by 21 · see citing works
Ignatiuk, V. M., Sharova, V., & Захарова, Л. А. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211057 · Cited by 14 · see citing works
“In addition, IL-6 can induce changes in the parameters affecting fetal growth, including nutrient transport, vascular permeability, and tissue oxygenation [189,190].”
Candia, A. A., Lean, S. C., Zhang, C. X. W., McKeating, D. R., Cochrane, A. L. K., Gulacsi, E., Herrera, E. A., Krause, B. J., & Sferruzzi-Perri, A. N. (2024) · Antioxidants · doi:10.3390/antiox13040411 · Cited by 17 · see citing works
Reginatto, M., Fontes, K. N., Monteiro, V., Silva, N., Andrade, C., Gomes, H. R., Império, G., Bloise, F., Kluck, G., Atella, G., et al. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.706499 · Cited by 16 · see citing works
“Treatment of trophoblast cells with cytokines, such as interleukin (IL)-1β and IL-6, elicited similar responses (Jones et al., 2009; Aye et al., 2013) indicating that infection may alter placental nutrient uptake and fetal transfer.”
BackgroundFornes, R., Manti, M., Qi, X., Vorontsov, E. A., Sihlbom, C., Nystrom, J. C., Jerlhag, E., Maliqueo, M. A., Hirschberg, A. L., Carlström, M., et al. (2019) · International Journal of Obesity · doi:10.1038/s41366-018-0314-8 · Cited by 19 · see citing works
Vumma, R., Johansson, J., & Venizelos, N. (2018) · Neuropsychobiology · doi:10.1159/000485130 · Cited by 16 · see citing works
Dubé, C., Aguer, C., Adamo, K. B., & Bainbridge, S. A. (2017) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2016-0446 · Cited by 19 · see citing works
“With respect to AA transport, IL-6 at physiological concentrations has been found to increase the expression of SNAT2 in cultured human primary placental trophoblast cells, resulting in increased activity of system A (Jones et al. 2009).”
Background
- Authors
- Jones, H. N., Jansson, T., & Powell, T. L.
- Affiliations
- University of Cincinnati (US)
- Corresponding author
- Jones, H. N.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2009-11
- Volume
- 297
- Issue
- 5
- Pages
- C1228-C1235
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2100179508
- Cited by
- 168
- References
- 42
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 12 · 2022: 7 · 2021: 6 · 2020: 12 · 2019: 10 · 2018: 7 · 2017: 13 · 2016: 9 · 2015: 18 · 2014: 12 · 2013: 13 · 2012: 9
- FWCI
- 6.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- College of Medicine, University of Cincinnati
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, TNF-α, system A amino acid transporter, SNAT2, SNAT1, STAT3 phosphorylation, trophoblast, placental nutrient transport, amino acid transport, inflammatory cytokines, fetal overgrowth, maternal diabetes, maternal obesity, JAK/STAT signaling
- MeSH terms
- Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Humans, Pregnancy, Trophoblasts, Tumor Necrosis Factor-alpha, Blotting, Western, Signal Transduction, Interleukin-6, Up-Regulation, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, Amino Acid Transport System A, STAT3 Transcription Factor
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