Hamdan Medical Journal (previously the Journal of Medical Sciences)

Table of Contents  

Interleukin 1 Receptor Antagonist and (IL-1Ra) IL-Ra Producing Mesenchymal Stem Cell in Therapy of Diabetes Mellitus

Vladislav Volarevic, Nebojsa Arsenijevic, Miodrag L. Lukic
Published in : Journal of Medical Sciences ; Vol 2, No 2 (2009)
DOI : 10.2174/1996327000902020052


Diabetes mellitus type 1 is an autoimmune disorder in which damage to beta cells are proposed to be due to abnormal T cell immune response.  Diabetes mellitus type 2 is an endocrine, metabolic disease in which the key metabolic abnormality is chronic hyperglycemia due to an imbalance between insulin production and insulin action. However, several lines of evidence suggest that there are shared mechanisms of beta cell dysfunction in both types of diabetes mellitus.

View article in  :   PDF    


Eizirik DL, Mandrup-Poulsen T. A choice of death. The signal transduction of immunemediated B-cell apoptosis. Diabetologia 2001; 44: 2115-2133.

DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabet Rev 1997; 5: 177–269.

Hani EH, Stoffers DA, Chèvre JC, et al. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest 1999; 104: R41-8.

Rother K. Diabetes treatment-bridging the divide. NEJM 2007, 356: 1499-1501.

Ortiz LA, Dutreil M, Fattman C, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007; 104: 11002-7.

Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR. A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol 1987; 139: 1546–1549.

Lukic ML, Stosic-Grujicic S, Ostojic N, Chan WL, Liew FY. Inhibition of nitric oxide generation affects the induction of diabetes by streptozotocin. Biochem Biophys Res Comm 15-178: 913 – 920.

Dinarello CA. The Role of the Interleukin-1– Receptor Antagonist in Blocking Inflammation Mediated by Interleukin-1. NEJM 2000; 343: 732-34.

Roux-Lombard P, Modoux C, Dayer JM. Production of interleukin-1 (IL-1) and a specific IL-1 inhibitor during human monocyte– macrophage differentiation: influence of GM-CSF. Cytokine 1989; 1: 45–51.

Kristensen M, Deleuran B, Eedy DJ, Feldmann M, Breathnac SM, Brennan FM. Distribution of interleukin 1 receptor antagonist protein (IRAP), interleukin 1 receptor, and interleukin 1 alpha in normal and psoriatic skin. Decreased expression of IRAP in psoriatic lesional epidermis. Br J Dermatol 1992; 127: 305–311.

Chan LS, Hammerberg C, Kang K, Sabb P, Tavakkol A, Cooper KD. Human dermal fibroblast interleukin-1 receptor antagonist (IL- 1ra) and interleukin-1 beta (IL-1 beta) mRNA and protein are co-stimulated by phorbol ester: implication for a homeostatic mechanism. J Invest Dermatol 1992; 99: 315–322.

Dewberry R, Holden H, Crossman D, Francis S. Interleukin-1 receptor antagonist expression in human endothelial cells and atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20: 2394–2400.

Juge-Aubry CE, Somm E, Chicheportiche R, et al. Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the production of IL-1 receptor antagonist by human adipose tissue. J Clin Endocrinol Metab 2004; 89: 2652–2658.

Perrier S, Kherratia B, Deschaumes C, et al. IL- 1ra and IL-1 production in human oral mucosal epithelial cells in culture: differential modulation by TGF-beta1 and IL-4. Clin Exp Immunol 2002; 127: 53–59.

Daig R, Rogler G, Aschenbrenner E, V, et al. Human intestinal epithelial cells secrete interleukin- 1 receptor antagonist and interleukin-8 but not interleukin-1 or interleukin-6. Gut 2000; 46: 350–358.

Gabay C, Smith MF, Eidlen D, Arend WP. Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein. J Clin Invest 1997; 99: 2930–2940.

Netea MG, Hancu N, Blok WL, et al. Interleukin 1 beta, tumour necrosis factor-alpha and interleukin 1 receptor antagonist in newly diagnosed insulin-dependent diabetes mellitus: comparison to long-standing diabetes and healthy individuals. Cytokine 1997; (4): 284-7.

Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Neilsenet JH. Affinity purified human interleukin-1 is cytotoxic to isolated islets of Langerhans. Diabetologia 1986; 29: 63-67.

Wilson CA, Jacobs C, Baker P, et al. Interleukin- 1 beta modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat. J Immunol 1990; 144: 3784-3788.

Wogensen LD, Reimers J, Nerup J, et al. Repetitive in vivo treatment with human recombinant interleukin-1 beta modifies beta cell function in normal rats. Diabetologia 1992; 35: 331-339.

Eizirik DL, Tracey DE, Bendtzen K, Sandler S. An interleukin-1 receptor antagonist protein protects insulin-producing beta cells against suppressive effects of interleukin-1 beta. Diabetologia 1991; 34: 445-8.

Stosic-Grujicic S, Lukic M, Ostajic N. Interleukin 1 receptor antagonists prevent the induction of experimental insulin-dependent autoimmune diabetes. Srp Arh Celok Lek 1994; 122 Suppl 1: 11-2.

Stosic-Grujicic S, Lukic ML. Glucocorticoidinduced keratinocyte-derived Interleukin-1 receptor antogonist. Immunology 1992; 75: 292-298.

Pfleger C, Mortensen HB, Hansen L, et al. Association of IL-1ra and adiponectin with Cpeptide and remission in patients with type 1 diabetes. Diabetes 2008; 57: 929-37.

Juge-Aubry CE, Somm E, Giusti V, et al. Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes 2003; 52: 1104– 1110.

Mandrup-Poulsen T, Zumsteg U, Reimers J, etal. Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. Cytokine 1993; 5: 185-91.

Sandberg JO, Andersson A, Eizirik DL, Sandlers S. Interleukin-1 receptor antagonist prevents low dose streptozotocin induced diabetes in mice. Bioshem Biophys Res Commun 1994; 202: 543-8.

Eizirik DL. Interleukin-1 beta induces an early decrease in insulin release, (pro) insulin biosynthesis and insulin mRNA in mouse pancreatic islets by a mechanism dependent on gene transcription and protein synthesis. Autoimmunity 1991; 10: 107-113.

Sandler S, Andersson A, Hellerstrom C. Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology 1987; 121: 1424-1431.

Giannoukakis N, Rudert WA, Trucco M, Robbins PD. Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an I kappa B repressor. J Biol Chem 2000; 275: 36509-36513.

Téllez N, Montolio M, Biarnés M, Castaño E, Soler J, Montanya E. Adenoviral overexpression of interleukin-1 receptor antagonist protein increases beta-cell replication in rat pancreatic islets. Gene Ther 2005; 12: 120-8.

Giannoukakis N, Rudert WA, Ghivizzani SC, etal. Adenoviral gene transfer of the Interleukin- 1 receptor antagonist protein to human islets prevents IL-1b–induced b-cell impairment and activation of islet cell Apoptosis in vitro. Diabetes 1999; 48: 1730-36.

Donath MY, Mandrup-Poulsen T. The use of interleukin-1-receptor antagonists in the treatment of diabetes mellitus. Nat Clin Pract Endocrinol Metab 2008; 4: 240-1.

Donath MY, Størling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T. Cytokines and betacell biology: from concept to clinical translation. Endocr Rev 2008; 29: 334-50.

Maedler K, Sergeev P, Ris F, et al. Glucoseinduced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002; 110: 851-60.

Ehses JA, Perren A, Eppler E, R, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 2007; 56: 2356-70.

Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care 2008; 31 Suppl 2: 161-4.

Böni-Schnetzler M, Thorne J, Parnaud G, et al. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J Clin Endocrinol Metab 2008; 93(10): 4065-74.

Sauter NS, Schulthess FT, Galasso R, Castellani LW, Maedler K. The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology 2008; 149: 2208-18.

Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus. NEJM 2007; 356: 1517-26.

Dinarello CA. The many worlds of reducing interleukin-1. Arthritis Rheum 2005; 52: 1960- 1967.

Porada CD, Zanjani ED, Almeida-Porad G. Adult mesenchymal stem cells: a pluripotent population with multiple applications Curr Stem Cell Res Ther 2006;1: 365-9.

Tyndall A, Walker UA, Cope A, et al. Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October 2005. Arthritis Res Ther 2007; 9: 301.

Gnecchi M, Melo LG. Bone marrow-derived mesenchymal stem cells: isolation, expansion, characterization, viral transduction, and production of conditioned medium. Methods Mol Biol 2009; 482: 281-94.

Delorme B, Charbord P. Culture and characterization of human bone marrow mesenchymalstem cells. Methods Mol Med 2007; 140: 67-81.

Yamamoto N, Akamatsu H, Hasegawa S, et al. Isolation of multipotent stem cells from mouse adipose tissue. J Dermatol Sci 2007; 48: 43-52.

Lu LL, Liu YJ, Yang SG, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesissupportive function and other potentials. Haematologica 2006; 91: 1017-26.

Bieback K, Klüter H. Mesenchymal stromal cells from umbilical cord blood. Curr Stem Cell Res Ther 2007; 2: 310-23.

da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119: 2204-13.

Short BJ, Brouard N, Simmons PJ. Prospective isolation of mesenchymal stem cells from mouse compact bone. Methods Mol Biol 2009; 482: 259-68.

Polisetty N, Fatima A, Madhira SL, Sangwan VS, Vemuganti GK. Mesenchymal cells from limbal stroma of human eye. Mol Vis 2008; 14: 431-42.

Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25: 2739–2749.

Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71–74.

Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 2008; 57: 1759-67.

Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 2005; 35: 1482–1490.

Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond) 2005; 2: 8.

Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34+- derived and monocyte-derived dendritic cells. J Immunol 2006; 177: 2080–2087.

Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499–3506.

Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H. Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol 2002; 80: 477-83.

Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 2008; 26: 212–222.

Deng W, Han Q, Liao L, You S, Deng H, Zhao RC. Effects of allogeneic bone marrowderived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol 2005; 24: 458–463.

Dayer JM, Burger D. Interleukin-1, tumor necrosis factor and their specific inhibitors. Eur Cytokine Netw 1994; 5: 563-71.

Cavaillon JM. Contribution of cytokines to inflammatory mechanisms. Pathol Biol (Paris) 1993; 41: 799-811.

Cavaillon JM, Haeffner-Cavaillon N. Cytokines and inflammation. Rev Prat 1993; 43: 547- 52.

Cavaillon JM. Cytokines in inflammation. C R Seances Soc Biol Fil 1995; 189: 531-44.

Lee RH, Seo MJ, Reger RL, et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 2006; 103: 17438-43.

Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ, Conget PA. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 2008; 14: 631-40.

Abdel Aziz MT, El-Asmar MF, Haidara M, et al. Effect of bone marrow-derived mesenchymal stem cells on cardiovascular complications in diabetic rats. Med Sci Monit 2008; 14: BR249-55.

Kwon DS, Gao X, Liu YB, et al. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J 2008; 5: 453-63.

Shibata T, Naruse K, Kamiya H, et al. Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes 2008; 57: 3099- 107.

Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007; 25: 371–379.

Breitbach M, Bostani T, Roell W, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007; 110: 1362– 1369.

Atsma DE, Fibbe WE, Rabelink TJ. Opportunities and challenges for mesenchymal stem cell-mediated heart repair. Curr Opin Lipidol 2007; 18: 645–649.

Add comment 

Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA