Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment

• Authors: Marek Cieślak , Andrzej Wojtczak , Michał Cieślak
• Languages of publication: EN

Abstracts

EN

Several relations between cytokines and pathogenesis of diabetes are reviewed. In type 1 and type 2 diabetes an increased synthesis is observed and as well as the release of pro-inflammatory cytokines, which cause the damage of pancreatic islet cells and, in type 2 diabetes, the development of the insulin resistance. That process results in the disturbed balance between pro-inflammatory and protective cytokines. Pro-inflammatory cytokines such as interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as recently discovered pancreatic derived factor PANDER are involved in the apoptosis of pancreatic β-cells. Inside β-cells, cytokines activate different metabolic pathways leading to the cell death. IL-1β activates the mitogen-activated protein kinases (MAPK), affects the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activates the inducible nitric oxide synthase (iNOS). TNF-α and IFN-γ in a synergic way activate calcium channels, what leads to the mitochondrial dysfunction and activation of caspases. Neutralization of pro-inflammatory cytokines, especially interleukin 1β with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1β antibodies might cause the extinction of the inflammatory process of pancreatic islets, and consequently normalize concentration of glucose in blood and decrease the insulin resistance. In type 1 diabetes interleukin-6 participates in regulation of balance between Th17 and regulatory T cells. In type 2 diabetes and obesity, the long-duration increase of IL-6 concentration in blood above 5 pg/ml leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in the insulin resistance in cells of the skeletal muscles, liver and adipose tissue.

Keywords

EN

interleukin 1β; interleukin-6; tumor necrosis factor-α; pancreatic derived factor; insulin resistance

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2015
• Volume: 62
• Issue: 1
• Pages: 15-21

Dates

published

2015

received

2014-07-06

revised

2015-02-01

accepted

2015-02-19

online

2015-03-18

Contributors

author

Marek Cieślak

• Neurology Department, WSZ Hospital in Toruń, Toruń, Poland

author

Andrzej Wojtczak

• Department of Crystallochemistry and Biocrystallography, Nicolaus Copernicus University in Toruń, Toruń, Poland

author

Michał Cieślak

• Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland

References

• Andersson AK, Börjesson A, Sandgren J, Sandler S (2005) Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets. Mol Cell Endocrinol 240: 50-57.
• Ahima RS (2006) Adipose tissue as an endocrine organ. Obesity (Silver Spring) 14 (Suppl 5): 242-249.
• Ahima RS, Osei SY (2008) Adipokines in obesity. Front Horm Res 36: 182-197.
• Asakawa H, Miyagawa J, Hanafusa T, Kuwajima M, Matsuzawa Y (1997) High glucose and hyperosmolarity increase secretion of interleukin-1 beta in cultured human aortic endothelial cells. J Diabetes Complications 11: 176-179.
• Bassols J, Ortega FJ, Moreno-Navarrete JM, Peral B, Ricart W, Fernández-Real JM (2009) Study of the proinflammatory role of human differentiated omental adipocytes. J Cell Biochem 107: 1107-1117.
• Bertelli E, Bendayan M (2005) Association between endocrine pancreas and ductal system. More than an epiphenomenon of endocrine differentiation and development? J Histochem Cytochem 53: 1071-1086.
• Bettelli E, Korn T, Kuchroo VK (2007) Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 19: 652-657.
• Böni-Schnetzler M, Boller S, Debray S, Bouzakri K, Meier DT, Prazak R, Kerr-Conte J, Pattou F, Ehses JA, Schuit FC, Donath MY (2009) Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150: 5218-5229.
• Burnstock G (2014) Purinergic signalling in endocrine organs. Purinergic Signal 10 189-231.
• Chang I, Cho N, Kim S, Kim JY, Kim E, Woo JE, Nam JH, Kim SJ, Lee MS (2004) Role of calcium in pancreatic islet cell death by IFN-gamma/TNF-alpha. J Immunol 172: 7008-7014.
• Chen H, Ren A, Hu S, Mo W, Xin X, Jia W (2007) The significance of tumor necrosis factor-alpha in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Res Clin Pract 75: 327-332.
• Cieślak M, Roszek K (2014) Purinergic signaling in the pancreas and the therapeutic potential of ecto-nucleotidases in diabetes. Acta Biochim Pol 61: 655-662.
• Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54 (Suppl 2): S97-S107.
• Dinarello CA, Donath MY, Mandrup-Poulsen T (2010) Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 17: 314-321.
• Donath MY, Böni-Schnetzler M, Ellingsgaard H, Ehses JA (2009) Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes. Physiology (Bethesda) 24: 325-331.
• Donath MY, Böni-Schnetzler M, Ellingsgaard H, Halban PA, Ehses JA (2010) Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab 21: 261-267.
• Donath MY, Mandrup-Poulsen T (2008) The use of interleukin-1-receptor antagonists in the treatment of diabetes mellitus. Nat Clin Pract Endocrinol Metab 4: 240-241.
• Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11: 98-107.
• Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, Kassis N, Irminger JC, Kergoat M, Portha B, Homo-Delarche F, Donath MY (2009) IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci USA 106: 13998-134003.
• Eizirik DL, Mandrup-Poulsen T (2001) A choice of death: the signal-transduction of immune-mediated β-cell apoptosis. Diabetologia 44: 2115-2133.
• Eizirik DL, Miani M, Cardozo AK (2013) Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56: 234-241.
• Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D (2002) Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106: 2067-2072.
• Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW (2004) Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145: 2273-2282.
• Giugliano D (2002) Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106: 2067-2072.
• Grieco FA, Moore F, Vigneron F, Santin I, Villate O, Marselli L, Rondas D, Korf H, Overbergh L, Dotta F, Marchetti P, Mathieu C, Eizirik DL (2014444) IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets. Diabetologia 57 502-511.
• Harding HP, Ron D (2002) Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51 (Suppl 3): S455-S461.
• Hotamisligil GS (2005) Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes 54 (Suppl 2): S73-S78.
• Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87-91.
• Kado S, Nagase T, Nagata N (1999) Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol 36: 67-72.
• Kaiser N, Leibowitz G, Nesher R (2003) Glucotoxicity and beta-cell failure in type 2 diabetes mellitus.J Pediatr Endocrinol Metab 16: 5-22.
• Kawasaki E, Abiru N, Eguchi K (2004) Prevention of type 1 diabetes: from the view point of beta cell damage. Diabetes Res Clin Pract 66 (Suppl 1): S27-32.
• Kim EK, Song MY, Hwang TO, Kim HJ, Moon WS, Ryu DG, So HS, Park R, Park JW, Kwon KB, Park BH (2008) Radix clematidis extract protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. Int J Mol Med 22: 349-356.
• Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40: 1830-1835.
• Kimura A, Naka T, Kishimoto T (2007) IL-6-dependent and -independent pathways in the development of interleukin 104-producing T helper cells. Proc Natl Acad Sci USA 104: 12099-12104.
• Klueh U, Antar O, Qiao Y, Kreutzer DL (2013) Role of interleukin-1/interleukin-1 receptor antagonist family of cytokines in long-term continuous glucose monitoring in vivo. J Diabetes Sci Technol 7: 1538-1546.
• Kwon G, Corbett JA, Hauser S, Hill JR, Turk J, McDaniel ML (1998) Evidence for involvement of the proteasome complex (26S) and NFkappaB in IL-1beta-induced nitric oxide and prostaglandin production by rat islets and RINm5F cells. Diabetes 47: 583-591.
• Lacraz G, Giroix MH, Kassis N, Coulaud J, Galinier A, Noll C, Cornut M, Schmidlin F, Paul JL, Janel N, Irminger JC, Kergoat M, Portha B, Donath MY, Ehses JA, Homo-Delarche F (2009) Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat. PLoS One 9: e6963.
• Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses J, Seifert B, Mandrup-Poulsen T, Donath M (2007) Interleukin-1 receptor antagonist-treatment of patients with type 2 diabetes. Ugeskr Laeger 169: 3868-3871.
• Larsen L, Størling J, Darville M, Eizirik DL, Bonny C, Billestrup N, Mandrup-Poulsen T (2005) Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor kappaB-mediated gene expression in insulin-producing INS-1E cells. Diabetologia 48: 2582-2590.
• Lee J. (2013) Adipose tissue macrophages in the development of obesity-induced inflammation, insulin resistance and type 2 diabetes. Arch Pharm Res 36: 208-22.
• Lv N, Song MY, Kim EK, Park JW, Kwon KB, Park BH (2008) Guggulsterone, a plant sterol, inhibits NF-kappaB activation and protects pancreatic beta cells from cytokine toxicity. Mol Cell Endocrinol 289: 49-59.
• Memon AA, Sundquist J, Wang X, Palmér K, Sundquist K, Bennet L (2013) The association between cytokines and insulin sensitivity in Iraqi immigrants and native Swedes. BMJ Open 29: e003473.
• Mirza S, Hossain M, Mathews C, Martinez P, Pino P, Gay JL, Rentfro A, McCormick JB, Fisher-Hoch SP (2012) Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine 57: 136-142.
• Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 82: 4196-4200.
• Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110: 851-860.
• Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136: 2348-2357.
• Movahedi B, Van de Casteele M, Caluwé N, Stangé G, Breckpot K, Thielemans K, Vreugdenhil G, Mathieu C, Pipeleers D (2004) Human pancreatic duct cells can produce tumour necrosis factor-alpha that damages neighbouring beta cells and activates dendritic cells. Diabetologia 47: 998-1008.
• Odegaard JI, Chawla A (2012) Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb Perspect Med 2: a007724.
• Ortis F, Cardozo AK, Crispim D, Störling J, Mandrup-Poulsen T, Eizirik DL (2006) Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. Mol Endocrinol 20: 1867-1879.
• Ortis F, Naamane N, Flamez D, Ladrière L, Moore F, Cunha DA, Colli ML, Thykjaer T, Thorsen K, Orntoft TF, Eizirik DL (2010) Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells. Diabetes 59: 358-374.
• Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T (2008) Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine 44: 141-148.
• Pickup JC, Chusney GD, Thomas SM, Burt D (2000) Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci 67: 291-300.
• Rouvier E, Luciani MF, Mattéi MG, Denizot F, Golstein P (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol 150: 5445-5456.
• Ryba-Stanisławowska M, Skrzypkowska M, Myśliwska J, Myśliwiec M (2013) The serum IL-6 profile and Treg/Th17 peripheral cell populations in patients with type 1 diabetes. Mediators Inflamm 2013: 205284.
• Sarvas JL, Khaper N, Lees SJ (2013) The IL-6 Paradox: Context Dependent Interplay of SOCS3 and AMPK. J Diabetes Metab Suppl 13 doi: 10.4172/2155-6156.S13-003.
• Sharma RB, Alonso LC. (2014) Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep 6: 492.
• Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116: 1793-1801.
• Song MY, Kim EK, Moon WS, Park JW, Kim HJ, So HS, Park R, Kwon KB, Park BH (2009) Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. Toxicol Appl Pharmacol 235: 57-67.
• Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC, Andrikopoulos S, Proietto J, Görgün CZ, Carling D, Hotamisligil GS, Febbraio MA, Kay TW, Kemp BE (2006) Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 4: 465-474.
• Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24: 5434-5446.
• Van Belle TL, Coppieters KT, von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91: 79-118.
• Wang C, Burkhardt BR, Guan Y, Yang J (2012) Role of pancreatic-derived factor in type 2 diabetes: evidence from pancreatic β cells and liver. Nutr Rev 70: 100-106.
• Wang C, Guan Y, Yang J (2010) Cytokines in the Progression of Pancreatic β-Cell Dysfunction. Int J Endocrinol 2010: 515136.
• Wieser V, Moschen AR, Tilg H (2013) Inflammation, cytokines and insulin resistance: a clinical perspective. Arch Immunol Ther Exp (Warsz) 61: 119-125.
• Wolf BA (2005) Structure-function studies of PANDER, an islet specific cytokine inducing cell death of insulin-secreting beta cells. Biochemistry 44: 11342-11352.
• Weir GC, Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53 (Suppl 3): S16-S21.
• Xiang JN, Chen DL, Yang LY (2012) Effect of PANDER in βTC6-cell lipoapoptosis and the protective role of exendin-4. Biochem Biophys Res Commun 421: 701-706.
• Xu W, Gao Z, Wu J, Wolf BA (2005) Interferon-gamma-induced regulation of the pancreatic derived cytokine FAM3B in islets and insulin-secreting betaTC3 cells. Mol Cell Endocrinol 240: 74-81.
• Yang J, Gao Z, Robert CE, Burkhardt BR, Gaweska H, Wagner A, Wu J, Greene SR, Young RA, Wolf BA (2005) Structure-function studies of PANDER, an islet specific cytokine inducing cell death of insulin-secreting beta cells. Biochemistry 44: 11342-11352.