3. Eisenbarth GS (1986) Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314: 1360–1368. 4. Schroppel B, Zhang N, Chen P, Chen D, Bromberg JS, et al. (2005) Role of donor-derived monocyte chemoattractant protein-1 in murine islet transplan- tation. J Am Soc Nephrol 16: 444–451. 5. Emamaullee JA, Shapiro AM (2007) Factors influencing the loss of beta-cell mass in islet transplantation. Cell Transplant 16: 1–8. 6. Uno S, Imagawa A, Saisho K, Okita K, Iwahashi H, et al. (2010) Expression of chemokines, CXC chemokine ligand 10 (CXCL10) and CXCR3 in the inflamed islets of patients with recent-onset autoimmune type 1 diabetes. Endocr J 57: 991–996. 7. Herder C, Baumert J, Thorand B, Koenig W, de Jager W, et al. (2006) Chemokines as risk factors for type 2 diabetes: results from the MONICA/ KORA Augsburg study, 1984–2002. Diabetologia 49: 921–929. 8. Martin AP, Rankin S, Pitchford S, Charo IF, Furtado GC, et al. (2008) Increased expression of CCL2 in insulin-producing cells of transgenic mice promotes mobilization of myeloid cells from the bone marrow, marked insulitis, and diabetes. Diabetes 57: 3025–3033. 9. Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, et al. (2002) Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med 8: 1414–1420. 10. Piemonti L, Leone BE, Nano R, Saccani A, Monti P, et al. (2002) Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation. Diabetes 51: 55–65. 11. Solomon M, Balasa B, Sarvetnick N (2010) CCR2 and CCR5 chemokine receptors differentially influence the development of autoimmune diabetes in the NOD mouse. Autoimmunity 43: 156–163. 12. Zineh I, Beitelshees AL, Silverstein JH, Haller MJ (2009) Serum monocyte chemoattractant protein-1 concentrations associate with diabetes status but not arterial stiffness in children with type 1 diabetes. Diabetes Care 32: 465–467. 13. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P (2007) Role of chemokines in endocrine autoimmune diseases. Endocr Rev 28: 492–520. 14. Kim SH, Cleary MM, Fox HS, Chantry D, Sarvetnick N (2002) CCR4-bearing T cells participate in autoimmune diabetes. J Clin Invest 110: 1675–1686. 15. Chen MC, Proost P, Gysemans C, Mathieu C, Eizirik DL (2001) Monocyte chemoattractant protein-1 is expressed in pancreatic islets from prediabetic NOD mice and in interleukin-1 beta-exposed human and rat islet cells. Diabetologia 44: 325–332. 16. Lazennec G, Richmond A (2010) Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med 16: 133–144. 17. Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 5: 219–226. 18. Del Guerra S, D’Aleo V, Gualtierotti G, Filipponi F, Boggi U, et al. (2010) A common polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene regulatory region influences MCP-1 expression and function of isolated human pancreatic islets. Transplant Proc 42: 2247–2249. 19. Kriegel MA, Rathinam C, Flavell RA (2012) Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c+ CD11b+ dendritic cells. Proc Natl Acad Sci U S A 109: 3457–3462. 20. Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132: 344–362. 21. Jacobs MD, Harrison SC (1998) Structure of an IkappaBalpha/NF-kappaB complex. Cell 95: 749–758. 22. Smale ST (2011) Hierarchies of NF-kappaB target-gene regulation. Nat Immunol 12: 689–694. 23. Kutlu B, Darville MI, Cardozo AK, Eizirik DL (2003) Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic beta-cells. Diabetes 52: 348–355. 24. Sekine O, Nishio Y, Egawa K, Nakamura T, Maegawa H, et al. (2002) Insulin activates CCAAT/enhancer binding proteins and proinflammatory gene expression through the phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. J Biol Chem 277: 36631–36639. 25. Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429: 403–417. 26. Kondo T, El Khattabi I, Nishimura W, Laybutt DR, Geraldes P, et al. (2009) p38 MAPK is a major regulator of MafA protein stability under oxidative stress. Mol Endocrinol 23: 1281–1290. 27. Kumar S, Boehm J, Lee JC (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2: 717–726. 28. Medicherla S, Protter AA, Ma JY, Mangadu R, Almirez R, et al. (2006) Preventive and therapeutic potential of p38 alpha-selective mitogen-activated protein kinase inhibitor in nonobese diabetic mice with type 1 diabetes. J Pharmacol Exp Ther 318: 99–107. 29. Tchen CR, Martins JR, Paktiawal N, Perelli R, Saklatvala J, et al. (2010) Glucocorticoid regulation of mouse and human dual specificity phosphatase 1 (DUSP1) genes: unusual cis-acting elements and unexpected evolutionary divergence. J Biol Chem 285: 2642–2652. 30. Clark AR, Martins JR, Tchen CR (2008) Role of dual specificity phosphatases in biological responses to glucocorticoids. J Biol Chem 283: 25765–25769. 31. Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, et al. (2001) Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 20: 7108–7116. Regulation of CCL2 Gene Expression 32. Beck IM, Vanden Berghe W, Vermeulen L, Yamamoto KR, Haegeman G, et al. (2009) Crosstalk in Inflammation: The Interplay of Glucocorticoid Receptor- Based Mechanisms and Kinases and Phosphatases. Endocr Rev. 33. Yamamoto KR (1985) Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 19: 209–252. 34. Shipp LE, Lee JV, Yu CY, Pufall M, Zhang P, et al. (2010) Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids. PLoS One 5: e13754. 35. Hohmeier HE, Mulder H, Chen G, Henkel-Rieger R, Prentki M, et al. (2000) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel- dependent and -independent glucose-stimulated insulin secretion. Diabetes 49: 424–430. 36. Janjic D, Maechler P, Sekine N, Bartley C, Annen AS, et al. (1999) Free radical modulation of insulin release in INS-1 cells exposed to alloxan. Biochem Pharmacol 57: 639–648. 37. Milburn JL Jr, Hirose H, Lee YH, Nagasawa Y, Ogawa A, et al. (1995) Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem 270: 1295–1299. 38. Burke SJ, Collier JJ (2011) The gene encoding cyclooxygenase-2 is regulated by IL-1beta and prostaglandins in 832/13 rat insulinoma cells. Cell Immunol 271: 379–384. 39. Herz J, Gerard RD (1993) Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc Natl Acad Sci U S A 90: 2812–2816. 40. Prasad RC, Wang XL, Law BK, Davis B, Green G, et al. (2009) Identification of genes, including the gene encoding p27Kip1, regulated by serine 276 phosphorylation of the p65 subunit of NF-kappaB. Cancer Lett 275: 139–149. 41. Jobin C, Panja A, Hellerbrand C, Iimuro Y, Didonato J, et al. (1998) Inhibition of proinflammatory molecule production by adenovirus-mediated expression of a nuclear factor kappaB super-repressor in human intestinal epithelial cells. J Immunol 160: 410–418. 42. Bueno OF, De Windt LJ, Lim HW, Tymitz KM, Witt SA, et al. (2001) The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo. Circ Res 88: 88–96. 43. Stewart MD, Johnson GA, Vyhlidal CA, Burghardt RC, Safe SH, et al. (2001) Interferon-tau activates multiple signal transducer and activator of transcription proteins and has complex effects on interferon-responsive gene transcription in ovine endometrial epithelial cells. Endocrinology 142: 98–107. 44. 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. 45. Collier JJ, Burke SJ, Eisenhauer ME, Lu D, Sapp RC, et al. (2011) Pancreatic beta-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis. PLoS One 6: e22485. 46. Jewell CM, Scoltock AB, Hamel BL, Yudt MR, Cidlowski JA (2012) Complex human glucocorticoid receptor dim mutations define glucocorticoid induced apoptotic resistance in bone cells. Mol Endocrinol 26: 244–256. 47. Westwell-Roper C, Dai DL, Soukhatcheva G, Potter KJ, van Rooijen N, et al. (2011) IL-1 blockade attenuates islet amyloid polypeptide-induced proinflam- matory cytokine release and pancreatic islet graft dysfunction. J Immunol 187: 2755–2765. 48. Chipitsyna G, Gong Q, Gray CF, Haroon Y, Kamer E, et al. (2007) Induction of monocyte chemoattractant protein-1 expression by angiotensin II in the pancreatic islets and beta-cells. Endocrinology 148: 2198–2208. 49. Thomas HE, Darwiche R, Corbett JA, Kay TW (2002) Interleukin-1 plus gamma-interferon-induced pancreatic beta-cell dysfunction is mediated by beta- cell nitric oxide production. Diabetes 51: 311–316. 50. Arnush M, Heitmeier MR, Scarim AL, Marino MH, Manning PT, et al. (1998) IL-1 produced and released endogenously within human islets inhibits beta cell function. J Clin Invest 102: 516–526. 51. O’Neill LA, Greene C (1998) Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J Leukoc Biol 63: 650–657. 52. Storling J, Juntti-Berggren L, Olivecrona G, Prause MC, Berggren PO, et al. (2011) Apolipoprotein CIII Reduces Proinflammatory Cytokine-Induced Apoptosis in Rat Pancreatic Islets via the Akt Prosurvival Pathway. Endocrinology 152: 3040–3048. 53. Kato A, Chustz RT, Ogasawara T, Kulka M, Saito H, et al. (2009) Dexamethasone and FK506 inhibit expression of distinct subsets of chemokines in human mast cells. J Immunol 182: 7233–7243. 54. Patterson KI, Brummer T, O’Brien PM, Daly RJ (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418: 475–489. 55. Guo Y, Xiao P, Lei S, Deng F, Xiao GG, et al. (2008) How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin (Shanghai) 40: 426–436. 56. Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354: 610–621. 57. Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392: 565–568. 58. Bertuzzi F, Marzorati S, Maffi P, Piemonti L, Melzi R, et al. (2004) Tissue factor and CCL2/monocyte chemoattractant protein-1 released by human islets affect islet engraftment in type 1 diabetic recipients. J Clin Endocrinol Metab 89: 5724–5728. PLOS ONE | www.plosone.org 18 October 2012 | Volume 7 | Issue 10 | e46986