The activation of the transcription factor NF-κB leads to changes in expression of many genes in pancreatic β-cells. However, the role of NF-κB activation in islet transplantation has not been fully elucidated. The aim of the present study was to investigate whether the state of NF-κB activation would influence the outcome of islet transplantation. Transgenic mice expressing a dominant active IKKβ (constitutively active) or a non-degradable form of IκBα (constitutive inhibition) under control of the rat insulin promoter were generated. Islets from these mice were transplanted into streptozotocin diabetic mice in suboptimal numbers. Further, the effects of salicylate (an inhibitor of NF-κB) treatment of normal islets prior to transplantation, and the effects of salicylate administration to mice prior to and after islet implantation were evaluated. Transplantation outcomes were not affected using islets expressing a non-degradable form of IκBα when compared to wild type controls. However, the transplantation outcomes using islets isolated from mice expressing a constitutively active mutant of NF-κB were marginally worse, although no aberrations of islet function in vitro could be detected. Salicylate treatment of normal islets or mice had no effect on transplantation outcome. The current study draws attention to the complexities of NF-κB in pancreatic beta cells by suggesting that they can adapt with normal or near normal function to both chronic activation and inhibition of this important transcription factor.
References
[1]
Padgett LE, Broniowska KA, Hansen PA, Corbett JA, Tse HM (2013) The role of reactive oxygen species and proinflammmmatory cytokines in type 1 diabetes pathogenesis. Ann N Y Acad Sci 1281: 16–35.
[2]
Rabinovitch A, Suarez-Pinzon WL (1998) Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 55: 1139–1149.
[3]
Mandrup-Poulsen T (1996) The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 39: 1005–1029.
[4]
Steer SA, Scarim AL, Chambers KT, Corbett JA (2006) Interleukin-1 stimulates beta-cell necrosis and release of the immmmunological adjuvant HMGB1. PLoS Med 3: e17.
[5]
Collier JJ, Fueger PT, Hohmeier HE, Newgard CB (2006) Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines. Diabetes 55: 1398–1406.
[6]
Giannoukakis N, Rudert WA, Trucco M, Robbins PD (2000) Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. J Biol Chem 275: 36509–36513.
[7]
Cardozo AK, Heimberg H, Heremans Y, Leeman R, Kutlu B, et al. (2001) A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells. J Biol Chem 276: 48879–48886.
[8]
Laybutt DR, Kaneto H, Hasenkamp W, Grey S, Jonas JC, et al. (2002) Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. Diabetes 51: 413–423.
[9]
Kwon G, Corbett JA, Rodi CP, Sullivan P, McDaniel ML (1995) Interleukin-1 beta-induced nitric oxide synthase expression by rat pancreatic beta-cells: evidence for the involvement of nuclear factor kappa B in the signaling mechanism. Endocrinology 136: 4790–4795.
[10]
Heimberg H, Heremans Y, Jobin C, Leemans R, Cardozo AK, et al. (2001) Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes 50: 2219–2224.
[11]
Zeender E, Maedler K, Bosco D, Berney T, Donath MY, et al. (2004) Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab 89: 5059–5066.
[12]
Chang I, Kim S, Kim JY, Cho N, Kim YH, et al. (2003) Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis. Diabetes 52: 1169–1175.
[13]
Papaccio G, Graziano A, d'Aquino R, Valiante S, Naro F (2005) A biphasic role of nuclear transcription factor (NF)-kappaB in the islet beta-cell apoptosis induced by interleukin (IL)-1beta. J Cell Physiol 204: 124–130.
[14]
Chen C, Moreno R, Samikannu B, Bretzel RG, Schmitz ML, et al. (2011) Improved intraportal islet transplantation outcome by systemic IKK-beta inhibition: NF-kappaB activity in pancreatic islets depends on oxygen availability. Am J Transplant 11: 215–224.
[15]
Mabley JG, Hasko G, Liaudet L, Soriano FG, Southan GJ, et al. (2002) NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes. J Endocrinol 173: 457–464.
[16]
Eldor R, Yeffet A, Baum K, Doviner V, Amar D, et al. (2006) Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci U S A 103: 5072–5077.
[17]
Rink JS, Chen X, Zhang X, Kaufman DB (2012) Conditional and specific inhibition of NF-kappaB in mouse pancreatic beta cells prevents cytokine-induced deleterious effects and improves islet survival posttransplant. Surgery 151: 330–339.
[18]
Ding X, Wang X, Xue W, Tian X, Li Y, et al. (2012) Blockade of the nuclear factor kappa B pathway prolonged islet allograft survival. Artif Organs 36: E21–E27.
[19]
Eldor R, Abel R, Sever D, Sadoun G, Peled A, et al. (2013) Inhibition of Nuclear Factor-kappaB Activation in Pancreatic beta-Cells Has a Protective Effect on Allogeneic Pancreatic Islet Graft Survival. PLoS One 8: e56924.
[20]
Sorelle JA, Itoh T, Peng H, Kanak MA, Sugimoto K, et al. (2013) Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation. Diabetologia 56: 814–824.
[21]
Takahashi T, Matsumoto S, Matsushita M, Kamachi H, Tsuruga Y, et al. (2010) Donor pretreatment with DHMEQ improves islet transplantation. J Surg Res 163: e23–e34.
[22]
Fiorina P, Shapiro AM, Ricordi C, Secchi A (2008) The clinical impact of islet transplantation. Am J Transplant 8: 1990–1997.
[23]
Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, et al. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immmmunosuppressive regimen. N Engl J Med 343: 230–238.
[24]
Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, et al. (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54: 2060–2069.
[25]
Baeuerle PA, Baltimore D (1988) I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242: 540–546.
[26]
DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388: 548–554.
[27]
Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265: 956–959.
[28]
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, et al. (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293: 1673–1677.
[29]
Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, et al. (2010) The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 152: 346–357.
[30]
Goldfine AB, Fonseca V, Jablonski KA, Chen YD, Tipton L, et al. (2013) Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med 159: 1–12.
[31]
Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, et al. (2004) IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119: 285–298.
[32]
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, et al. (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11: 183–190.
[33]
Heitmeier MR, Scarim AL, Corbett JA (1997) Interferon-gamma increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1. J Biol Chem 272: 13697–13704.
[34]
Heitmeier MR, Scarim AL, Corbett JA (1999) Prolonged STAT1 activation is associated with interferon-gamma priming for interleukin-1-induced inducible nitric-oxide synthase expression by islets of Langerhans. J Biol Chem 274: 29266–29273.
[35]
Gotoh M, Maki T, Kiyoizumi T, Satomi S, Monaco AP (1985) An improved method for isolation of mouse pancreatic islets. Transplantation 40: 437–438.
[36]
Montana E, Bonner-Weir S, Weir GC (1993) Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J Clin Invest 91: 780–787.
[37]
Andersson A, Sandler S (1983) Viability tests of cryopreserved endocrine pancreatic cells. Cryobiology 20: 161–168.
[38]
Tillmar L, Carlsson C, Welsh N (2002) Control of insulin mRNA stability in rat pancreatic islets. Regulatory role of a 3′-untranslated region pyrimidine-rich sequence. J Biol Chem 277: 1099–1106.
[39]
Bottino R, Balamurugan AN, Tse H, Thirunavukkarasu C, Ge X, et al. (2004) Response of human islets to isolation stress and the effect of antioxidant treatment. Diabetes 53: 2559–2568.
[40]
Abdelli S, Ansite J, Roduit R, Borsello T, Matsumoto I, et al. (2004) Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure. Diabetes 53: 2815–2823.
[41]
Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, et al. (1996) Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function. Diabetes 45: 1161–1167.
[42]
Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, et al. (2012) The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase. Science.
[43]
McCall MD, Pawlick R, Shapiro AM (2011) Resveratrol fails to improve marginal mass engraftment of transplanted islets of Langerhans in mice. Islets 3..
[44]
Borthwick GM, Johnson AS, Partington M, Burn J, Wilson R, et al. (2006) Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism. FASEB J 20: 2009–2016.
[45]
Norlin S, Ahlgren U, Edlund H (2005) Nuclear factor-{kappa}B activity in {beta}-cells is required for glucose-stimulated insulin secretion. Diabetes 54: 125–132.
[46]
Jonas JC, Sharma A, Hasenkamp W, Ilkova H, Patane G, et al. (1999) Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes. J Biol Chem 274: 14112–14121.
[47]
Laybutt DR, Glandt M, Xu G, Ahn YB, Trivedi N, et al. (2003) Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. J Biol Chem 278: 2997–3005.
[48]
Hammar EB, Irminger JC, Rickenbach K, Parnaud G, Ribaux P, et al. (2005) Activation of NF-kappaB by extracellular matrix is involved in spreading and glucose-stimulated insulin secretion of pancreatic beta cells. J Biol Chem 280: 30630–30637.
