Methylglyoxal modulates immune responses: relevance to diabetes
Claire L Price, Hafid O S Al Hassi, Nicholas R English, Alexandra I F Blakemore, Andrew J Stagg, Stella C Knight, Claire L Price, Hafid O S Al Hassi, Nicholas R English, Alexandra I F Blakemore, Andrew J Stagg, Stella C Knight
Abstract
Increased methylglyoxal (MG) concentrations and formation of advanced glycation end-products (AGEs) are major pathways of glycaemic damage in diabetes, leading to vascular and neuronal complications. Diabetes patients also suffer increased susceptibility to many common infections, the underlying causes of which remain elusive. We hypothesized that immune glycation damage may account for this increased susceptibility. We previously showed that the reaction mixture (RM) for MG glycation of peptide blocks up regulation of CD83 in myeloid cells and inhibits primary stimulation of T cells. Here, we continue to investigate immune glycation damage, assessing surface and intracellular cytokine protein expression by flow cytometry, T-cell proliferation using a carboxyfluorescein succinimidyl ester assay, and mRNA levels by RT-PCR. We show that the immunomodulatory component of this RM was MG itself, with MG alone causing equivalent block of CD83 and loss of primary stimulation. Block of CD83 expression could be reversed by MG scavenger N-acetyl cysteine. Further, MG within RM inhibited stimulated production of interleukin (IL)-10 protein from myeloid cells plus interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha from T cells. Loss of IL-10 and IFN-gamma was confirmed by RT-PCR analysis of mRNA, while TNF-alpha message was raised. Loss of TNF-alpha protein was also shown by ELISA of culture supernatants. In addition, MG reduced major histocompatibility complex (MHC) class I expression on the surface of myeloid cells and increased their propensity to apoptose. We conclude that MG is a potent suppressor of myeloid and T-cell immune function and may be a major player in diabetes-associated susceptibility to infection.
Figures
References
- Thornalley PJ. Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems-role in ageing and disease. Drug Metabol Drug Interact. 2008;23:125–50.
- Kalapos MP. The tandem of free radicals and methylglyoxal. Chem Biol Interact. 2008;171:251–71.
- Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest. 2001;108:949–55.
- Muller LM, Gorter KJ, Hak E, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41:281–8.
- Pozzilli P, Leslie RD. Infections and diabetes: mechanisms and prospects for prevention. Diabet Med. 1994;11:935–41.
- Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–96.
- Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.
- Cutler CW, Jotwani R, Pulendran B. Dendritic cells: immune saviors or Achilles’ heel. Infect Immun. 2001;69:4703–8.
- Price CL, Sharp PS, North ME, et al. Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells. Diabetes. 2004;53:1452–8.
- Lo TW, Westwood ME, McLellan AC, et al. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin. J Biol Chem. 1994;269:32299–305.
- Maldonado-Lopez R, De Smedt T, Michel P, et al. CD8alpha+ and CD8alpha- subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med. 1999;189:587–92.
- Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science. 1999;283:1183–6.
- Long EO. Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev. 2008;224:70–84.
- McLellan AC, Thornalley PJ, Benn J, Sonksen PH. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci (Lond) 1994;87:21–9.
- Beisswenger PJ, Howell SK, Touchette AD, et al. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes. 1999;48:198–202.
- Chaplen FW, Fahl WE, Cameron DC. Evidence of high levels of methylglyoxal in cultured Chinese hamster ovary cells. Proc Natl Acad Sci U S A. 1998;95:5533–8.
- Fujimoto Y, Tedder TF. CD83: a regulatory molecule of the immune system with great potential for therapeutic application. J Med Dent Sci. 2006;53:85–91.
- Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180:5771–7.
- Lohmann T, Laue S, Nietzschmann U, et al. Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. Diabetes. 2002;51:2474–80.
- Sakowicz-Burkiewicz M, Kocbuch K, Grden M, et al. Diabetes-induced decrease of adenosine kinase expression impairs the proliferation potential of diabetic rat T lymphocytes. Immunology. 2006;118:402–12.
- Avanzini MA, Ciardelli L, Lenta E, et al. IFN-gamma low production capacity in type 1 diabetes mellitus patients at onset of disease. Exp Clin Endocrinol Diabetes. 2005;113:313–7.
- Kukreja A, Cost G, Marker J, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002;109:131–40.
- Halminen M, Simell O, Knip M, Ilonen J. Cytokine expression in unstimulated PBMC of children with type 1 diabetes and subjects positive for diabetes-associated autoantibodies. Scand J Immunol. 2001;53:510–3.
- Price CL, Knight SC. Advanced glycation: a novel outlook on atherosclerosis. Curr Pharm Des. 2007;13:3681–7.
- Bidmon C, Frischmann M, Pischetsrieder M. Analysis of DNA-bound advanced glycation end-products by LC and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;853:51–8.
- Rabbani N, Thornalley PJ. The dicarbonyl proteome: proteins susceptible to dicarbonyl glycation at functional sites in health, aging, and disease. Ann N Y Acad Sci. 2008;1126:124–7.
- Iberg N, Fluckiger R. Nonenzymatic glycosylation of albumin in vivo. Identification of multiple glycosylated sites. J Biol Chem. 1986;261:13542–5.
- Gallet X, Charloteaux B, Thomas A, Brasseur R. A fast method to predict protein interaction sites from sequences. J Mol Biol. 2000;302:917–26.
- Zeng J, Dunlop RA, Rodgers KJ, Davies MJ. Evidence for inactivation of cysteine proteases by reactive carbonyls via glycation of active site thiols. Biochem J. 2006;398:197–206.
Source: PubMed