Bisphenol A (BPA) is used in huge amounts for many plastic products and is a hormone (estrogen) disrupting agent. BPA as well as FFAs may be deleterious for the immune system. The aim was to identify Th2 cytokines and some of their signal transduction mechanisms in INS-1 cells, an insulin secreting cell line. Screening using a proteome profile indicated an increase of IL-1, IL-2, IL-4, IL-6, IL-10, IL-13 and IL-17 by BPA. Also FFAs (in combination with LPS) were positive. In detailed quantitative measurements, these results were confirmedly indicating a complex array of pro-and anti-inflammatory potential. The interaction of BPA with 17 β -estradiol was non-additive with respect to IL-4 and IL-6 release and additive with respect to FFA interaction indicating same and different mechanisms of action, respecttively. As signal transduction PI3K (Wortmannin-sensitive) and STAT-3/6 (Tofacitinib-sensitive) are involved in various effects, INS-1 cells release several cytokines due to BPA and FFA attack which may be involved in disturbance of glucose homoeostasis and type 1 diabetes.
KeywordsBisphenol ATh2 CytokinesINS-1 Cells
German Environmental Surveys, Umweltbundesamt, 2009. www.umweltbundesamt.de
F. Mauvais-Jarvis, D. J. Cleqq and A. L. Hevener, “The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis,” Endocrine Reviews, Vol. 34, No. 3, 2013, p. 309. doi:10.1210/er.2012-1055
P. Alonso-Magdalena, A. B. Ropero, M. P. Carrera, C. R. Cederroth, M. Baquié, B. R. Gauthier, S. Nef, E. Stefani and A. Nadal, “Pancreatic Insulin Content Regulation by the Estrogen Receptor Eralpha,” PLoS ONE, Vol. 3, No. 4, 2008, Article ID: e2069. doi:10.1371/journal.pone.0002069
A. D. Papaconstantinou, B. R. Fisher, T. H. Umbreit, P. L. Goering, N. T. Lappas and K. M. Brown, “Effects of β-Estradiol and Bisphenol A on Heat Shock Protein Levels and Localization in the Mouse Uterus Are Antagonized by the Antiestrogen ICI 182,780,” Toxicol Sciences Vol, 63, No. 2, 2001, pp. 173-180. doi:10.1093/toxsci/63.2.173
D. Melzer, P. Gates, N. J. Osborne, W. E. Henley, R. Cipelli, A. Young, C. Money, P. McCormack, P. Schofield, D. Mosedale, D. Grainger and T. S. Galloway, “Urinary Bisphenol a Concentration and Angiography-Defined Coronary Artery Stenosis,” PLoS ONE, Vol. 7, No. 8, 2012, Article ID: e43378. doi:10.1371/journal.pone.0043378
K. M. Donogue, R. L. Miller, M. S. Perzanowski, A. C. Just, L. A. Hoepner, S. Arunajadai, S. Canfield, D. Resnick, A. M. Calafat, F. P. Perera and R. M. Whyatt, “Prenatal and Postnatal Bisphenol A Exposure and Asthma Development Among Inner-City Children,” The Journal of Allergy and Clinical Immunology, Vol. 131, No. 3, 2013, pp. 736-742. doi:10.1016/j.jaci.2012.12.1573
J.-Y. Youn, H.-Y. Park, J.-W. Lee, I.-O. Jun, K.-H. Choi, K. Kim and K.-H. Cho, “Evaluation of the Immune Response Following Exposure of Mice to Bisphenol A: Induction of Th1 Cytokine and Prolactin by BPA Exposure in the Mouse Spleen Cells,” Archives of Pharmacal Research, Vol. 25, No. 6, 2002, pp. 946-953. doi:10.1007/BF02977018
L. Trasande, T. M. Attina and J. Blustein, “Association between Urinary Bisphenol A Concentration and Obesity Prevalence in Children and Adolescents,” The Journal of American Medical Association, Vol. 308, No. 11, 2012, pp. 1113-1121. doi:10.1001/2012.jama.11461
L. Lynch, M. Nowak, B. Varghese, J. Clark, A. E. Hogan, V. Toxavidis, S. P. Balk, D. O′Shea, C. O′Farrelly and M. A. Exley, “Adipose Tissue Invariant NKT Cells Protect against Diet-Induced Obesity and Metabolic Disorder through Regulatory Cytokine Production,” Immunity, Vol. 37, No. 3, 2012, pp. 574-587. doi:10.1016/j.immuni.2012.06.016
S. J. Miyagi and A. C. Collier, “Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4,” Drug Metabolism Dispossition, Vol. 35, No. 9, 2007, pp. 1587-1592. doi:10.1124/dmd.107.015214
W. Dekant and W. Volkel, “Human Exposure to Bisphenol A by Biomonitoring: Methods, Results and Assessment of Environmental Exposures,” Toxicology and Applied Pharmacology, Vol. 228, No. 1, 2008, pp. 114-134. doi:10.1016/j.taap.2007.12.008
A. Calafat, “BPA Biomonitoring and Biomarker Studies,” FAO/WHO Expert Meeting on Bisphenol A (BPA), Geneva, 2-5 November 2010.
A. M. Calafat, J. Weuve, X. Ye, L. T. Jia, H. Hu, S. Ringer, K. Huttner, R. Hauser, et al., “Exposure to Bisphenol A and Other Phenols in Neonatal Intensive Care Unit Premature Infants,” Environmental Health Perspectives, Vol. 117, No. 4, 2009, pp. 639-644.
K. Becker, T. Goen, M. Seiwert, A. Conrad, H. Pick-Fuss, J. Muller, M. Wittassek, C. Schulz and M. Kolossa-Gehring, “GerES IV: Phthalate Metabolites and Bisphenol A in Urine of German Children,” International Journal of Hygiene and Environmental Health, Vol. 212, No. 6, 2009, pp. 685-692. doi:10.1016/j.ijheh.2009.08.002
R. W. Snyder, et al., “Metabolism and Disposition of Bisphenol A in Female Rats,” Toxicology and Applied Pharmacology, Vol. 168, No. 3, 2000, pp. 225-234. doi:10.1006/taap.2000.9051
H. Mielke and U. Gundert-Remy, “Bisphenol A Levels in Blood Depend on Age and Exposure,” Toxicology Letters, Vol. 190, No. 1, 2009, pp. 32-40. doi:10.1016/j.toxlet.2009.06.861
P. Stolba, M. Kvapil, D. Wichterle and P. Dvorák, “Kinetics of Free Fatty Acids in Hypertriglyceridemia. Evidence for Different Types of Insulin Resistance,” Annals of the New York Academy of Sciences, Vol. 683, No. 3, 1993, pp. 373-374. doi:10.1111/j.1749-6632.1993.tb35738.x
M. Zeyda, J. Huber, G. Prager and T. M. Stulnig, “Inflammation Correlates with Markers of T-Cell Subsets Including Regulatory T Cells in Adipose Tissue from Obese Patients,” Obesity, Vol. 19, No. 4, 2011, pp. 743-748. doi:10.1038/oby.2010.123
M. Igoillo-Esteve, L. Marselli, D. A. Cunha, L. Ladrière, F. Ortis, F. A. Grieco, F. Dotta, G. C. Weir, P. Marchetti, D. L. Eizirik and M. Cnop, “Palmitate Induces a Pro-Inflammatory Response in Human Pancreatic Islets that Mimics CCL2 Expression by Beta Cells in Type 2 Diabetes,” Diabetologia, Vol. 53, No. 7, 2010, pp. 1395-1405. doi:10.1007/s00125-010-1707-y
G. Boden, “Interaction between Free Fatty Acids and Glucose Metabolism,” Current Opinion in Clinical Nutrition and Metabolic Care, Vol. 5, No. 5, 2002, pp. 545-549. doi:10.1097/00075197-200209000-00014
G. Boden, P. She, M. Mozzoli, P. Cheung, K. Gumireddy, P. Reddy, X. Xiang, Z. Luo and N. Ruderman, “Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor-κB Pathway in Rat Liver,” Diabetes, Vol. 54, No. 12, 2005, pp. 3458-3465. doi:10.2337/diabetes.54.12.3458
B. M. Burgering and P. J. Coffer, “Protein Kinase B (c-Akt) in Phosphatidylinositol-3-OH Kinase Signal Transduction,” Nature, Vol. 376, No. 6541, 1995, pp. 599-602. doi:10.1038/376599a0
R. Meshkani and K. Adeli, “Hepatic Insulin Resistance, Metabolic Syndrome and Cardiovascular Disease,” Clinical Biochemistry, Vol. 42, No. 13-14, 2009, pp. 1331-1346. doi:10.1016/j.clinbiochem.2009.05.018
D. Janjic and M. Asfari, “Effects of Cytokines on Rat Insulinoma INS-1 Cells,” Journal of Endocrinology, Vol. 132, 1992, pp. 67-76. doi:10.1677/joe.0.1320067
M. Cnop, N. Welsh, J.-C. Jonas, A. Jorns, S. Lenzen and D. L. Eizirik, “Mechanism of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes. Many Differences, Few Similarities,” Diabetes, Vol. 54, Suppl. 2, 2005, pp. S97-S107. doi:10.2337/diabetes.54.suppl_2.S97
K. Madler, G. Dharmadhikari, D. M. Schumann and J. Storling, “Interleukin-Targeted Therapy for Metabolic Syndrome and Type 2 Diabetes,” Handbook of Experimental Pharmacology, Vol. 203, 2011, pp. 257-278.
T. Adachi, K. Yasuda, C. Mori, M. Yoshinaga, N. Aoki, G. Tsujimoto and K. Tsuda, “Promoting Insulin Secretion in Pancreatic Islets by Means of Bisphenol A and Nonylphenol via Intracellular Estrogen Receptors,” Food and Chemical Toxicology, Vol. 43, No. 5, 2005, pp. 713-719. doi:10.1016/j.fct.2005.01.009
H. Liang, Z. Wang and L. Gan, “Effect of Estrogen on Pancreatic β Cells,” Yixue Fenzi Shengwuxue Zazhi, Vol. 5, No. 23, 2008, pp. 535-538.
J. S. Rosa, S. Heydari, S. R. Oliver, R. L. Flores, A. M. Pontello, M. Ibardolaza and P. R. Galassetti, “Inflammatory Cytokine Profiles during Exercise in Obese, Diabetic, and Healthy Children,” Journal of Clinical Research in Pediatric Endocrinology, Vol. 3, No. 3, 2011, pp. 115-121. doi:10.4274/jcrpe.v3i3.23
Q. S. Mi, D. Ly, P. Zucker, M. McGarry and T. L. Delovitch, “Interleukin-4 But not Interleukin-10 Protects against Spontaneous and Recurrent Type 1 Diabetes by Activated CD1d-Restricted Invariant Natural Killer TCells,” Diabetes, Vol. 53, No. 5, 2004, pp. 1303-1310. doi:10.2337/diabetes.53.5.1303
G. Targher, L. Zenari, L. Bertolini, M. Muggeo and G. Zoppini, “Elevated Levels of Interleukin-6 in Young Adults with Type 1 Diabetes without Clinical Evidence of Microvascular and Macrovascular Complications,” Diabetes Care, Vol. 24, No. 5, 2001, pp. 956-957. doi:10.2337/diacare.24.5.956
J. K. Snell-Bergeon, N. A. West, E. J. Mayer-Davis, A. D. Liese, S. M. Marcovina, R. B. D`Agostino, R. F. Hamman and D. Dabelea, “Inflammatory Markers Are Increased in Youth with Type 1 Diabetes: The SEARCH Case-Control Study,” Journal of Endocrinology and Metabolism, Vol. 95, No. 6, 2010, pp. 2868-2876. doi:10.1210/jc.2009-1993
J. Yang, Y. Wang, Y. Gao, J. Shao, X. J. Zhang and Z. Yao, “Reciprocal Regulation of 17β-Estradiol, Interleukin-6 and Interleukin-8 during Growth and Progression of Epithel Ovarian Cancer,” Cytokine, Vol. 46, No. 3, 2009, pp. 382-391. doi:10.1016/j.cyto.2009.03.013
A. Oberbach, N. Schlichting, M. Blüher, P. Kovacs, H. Till, J. U. Stolzenburg and J. Neuhaus, “Palmitate Induced IL-6 and MCP-1 Expression in Human Bladder Smooth Muscle Cells Provides a Link between Diabetes and Urinary Tract Infections,” PLoS ONE, Vol. 5, No. 5, 2010, Article ID: e10882.
C. Weigert, K. Brodbeck, H. Staiger, C. Kausch, F. Machicao, H. U. Haring and E. D. Schleicher, “Palmitate, but not Unsaturated Fatty Acids, Induces the Expression of Interleukin-6 in Human Myotubes Through Proteasome-Dependent Activation of Nuclear Factor-kappaB,” Journal of Biological Chemistry, Vol. 279, No. 23, 2004, pp. 23942-23952. doi:10.1074/jbc.M312692200
J. Saraiva, E. Sola, D. Prieto and M. J. Antunes, “Diabetes as an Outcome Predictor after Heart Transplantation,” Interactive Cardiovasc Thoracic Surgery, Vol. 13, No. 5, 2011, pp. 499-504. doi:10.1510/icvts.2010.256321
N. C. Schloot, P. Hanifi-Mogghaddam, C. Goebel, S. V. Shatavi, S. Flohé, H. Kolb, H. Rothe, “Serum IFN-Gamma and IL-10 Levels Are Associated with Disease Pro-gression in Non-Obese Diabetic Mice,” Diabetes/ Metabolism Research and Reviews, Vol. 18, No. 1, 2002, pp. 64-70. doi:10.1002/dmrr.256
K. Saegusa, S. Yotsumoto, S. Kato and Y. Aramaki, “Phosphatidylinositol 3-Kinase-Mediated Regulation of IL-10 and IL-12 Production in Macrophages Stimulated with CpG Oligodeoxynucleotide,” Molecular Immunology, Vol. 44, No. 6, 2007, pp. 1323-1330. doi:10.1016/j.molimm.2006.05.008
A. Strom, B. Menart, M.-C. Simon, M. N. Pham, H. Kolb, M. Roden, P. Pozzilli, R. D. G. Leslie and N. C. Schloot, “Cellular Interferon-Gamma and Interleukin-13 Immune Reactivity in Type 1, Type 2 and Latent Autoimmune Diabetes: Action LADA 6,” Cytokine, Vol. 58, No. 2, 2012, pp. 148-151. doi:10.1016/j.cyto.2012.01.002
J. Honkanen, J. K. Nieminen, R. Gao, K. Luopajarvi, H. M. Salo, J. Ilonen, M. Knip, T. Otonkosi and O. Vaarala, “IL-17 Immunity in Human Type 1 Diabetes,” Journal of Immunology, Vol. 185, No. 3, 2010, pp. 1959-1967. doi:10.4049/jimmunol.1000788
G.-S. Jeong and D.-S. Lee, “Sauchinone Protects Pancreatic β-Cells against Cytokine-Mediated Toxicity,” Toxicology in Vitro, Vol. 25, No. 2, 2011, pp. 505-512. doi:10.1016/j.tiv.2010.12.004
K. Takeda, T. Tanaka, W. Shi, M. Matsumoto, M. Minami, S. Kashiwamura, K. Nakanishi, N. Yoshida, T. Kishimoto and S. Akira, “Essential Role of Stat6 in IL-4 Signalling,” Nature, Vol. 380, No. 6575, 1996, pp. 627-630. doi:10.1038/380627a0
T. Andus, T. Geiger, T. Hirano, T. Kishimoto, T.-A. Tran-Thi, K. Decker and P. C. Heinrich, “Regulation of Synthesis and Secretion of Major Rat Acute-Phase Proteins by Recombinant Human Interleukin-6 (BSF-2/IL-6) in Hepatocyte Primary Cultures,” European Journal of Biochemistry, Vol. 173, No. 2, 1988, pp. 287-293. doi:10.1111/j.1432-1033.1988.tb13997.x
J. G. Bode and P. C. Heinrich, “Interleukin-6 Signaling during the Acute-Phase Response of the Liver,” In: I. Arias, A. Wolkoff, J. Boyer, D. Shafritz, N. Fausto, H. Alter and D. Cohen, Eds., The Liver: Biology and Pathobiology, 4th Edition, Lippincott Williams Wilkins, Philadelphia, 2001, pp. 565-580.
W. Volkel, N. Bittner and W. Dekant, “Quantitation of Bisphenol A and Bisphenol A Glucuronide in Biological Samples by High Performance Liquid Chromatography-Tandem Mass Spectrometry,” Drug Metabolism and Disposition, Vol. 39, No. 11, 2005, pp. 1748-1757. doi:10.1124/dmd.105.005454