High glucose concentrations induce TNF-α production through the down-regulation of CD33 in primary human monocytes

BMC Immunology

Martha Torres³  Eduardo Sada³  Silvia Guzmán-Beltrán³  Karen Bobadilla³  E Martha Pérez-Armendariz²  Guadalupe Fabián⁴  Lourdes Garcia-Garcia¹  Gloria Soldevila⁵  M Teresa Herrera³  Yolanda Gonzalez³ 

[1] Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Av. Universidad 655, Cuernavaca, 62508, México;Departamento de Medicina Experimental, Universidad Nacional Autónoma de México, Ciudad Universitaria 04510, Ciudad de México, 70228, México;Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, Ciudad de México, 14080, México;Clínica del Síndrome Metabólico, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, Ciudad de México, 14080, México;Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria 04510, Ciudad de México, 70228, México

关键词: Type 2 diabetes;    Siaglec-3;    ROS;    Monocytes;    Cytokines;    Antioxidant;   

Others  :  1077925
DOI  :  10.1186/1471-2172-13-19

 received in 2011-12-08, accepted in 2012-04-14,  发布年份 2012

【 摘 要 】

Background

CD33 is a membrane receptor containing a lectin domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) that is able to inhibit cytokine production. CD33 is expressed by monocytes, and reduced expression of CD33 correlates with augmented production of inflammatory cytokines, such as IL-1β, TNF-α, and IL-8. However, the role of CD33 in the inflammation associated with hyperglycemia and diabetes is unknown. Therefore, we studied CD33 expression and inflammatory cytokine secretion in freshly isolated monocytes from patients with type 2 diabetes. To evaluate the effects of hyperglycemia, monocytes from healthy donors were cultured with different glucose concentrations (15-50 mmol/l D-glucose), and CD33 expression and inflammatory cytokine production were assessed. The expression of suppressor of cytokine signaling protein-3 (SOCS-3) and the generation of reactive oxygen species (ROS) were also evaluated to address the cellular mechanisms involved in the down-regulation of CD33.

Results

CD33 expression was significantly decreased in monocytes from patients with type 2 diabetes, and higher levels of TNF-α, IL-8 and IL-12p70 were detected in the plasma of patients compared to healthy donors. Under high glucose conditions, CD33 protein and mRNA expression was significantly decreased, whereas spontaneous TNF-α secretion and SOCS-3 mRNA expression were increased in monocytes from healthy donors. Furthermore, the down-regulation of CD33 and increase in TNF-α production were prevented when monocytes were treated with the antioxidant α-tocopherol and cultured under high glucose conditions.

Conclusion

Our results suggest that hyperglycemia down-regulates CD33 expression and triggers the spontaneous secretion of TNF-α by peripheral monocytes. This phenomenon involves the generation of ROS and the up-regulation of SOCS-3. These observations support the importance of blood glucose control for maintaining innate immune function and suggest the participation of CD33 in the inflammatory profile associated with type 2 diabetes.

【 授权许可】

   
2012 Gonzalez et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002, 106:2067-2072.
• [2]Temelkova-Kurktschiev T, Henkel E, Koehler C, Karrei K, Hanefeld M: Subclinical inflammation in newly detected Type II diabetes and impaired glucose tolerance. Diabetologia 2002, 45:151.
• [3]Morohoshi M, Fujisawa K, Uchimura I, Numano F: Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes 1996, 45:954-959.
• [4]Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE: Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 2004, 53:2079-2086.
• [5]Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G: Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2003, 52:1799-1805.
• [6]Devaraj S, Jialal I: Increased secretion of IP-10 from monocytes under hyperglycemia is via the TLR2 and TLR4 pathway. Cytokine 2009, 47:6-10.
• [7]Satoh N, Shimatsu A, Himeno A, Sasaki Y, Yamakage H, Yamada K, Suganami T, Ogawa Y: Unbalanced M1/M2 phenotype of peripheral blood monocytes in obese diabetic patients: effect of pioglitazone. Diabetes Care 2010, 33:e7.
• [8]Gacka M, Dobosz T, Szymaniec S, Bednarska-Chabowska D, Adamiec R, Sadakierska-Chudy A: Proinflammatory and atherogenic activity of monocytes in type 2 diabetes. J Diabetes Complications 2010, 24:1-8.
• [9]Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C: Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res ClinPract 2007, 77:47-57.
• [10]Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S: Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond) 2006, 20:1366-1369.
• [11]Devaraj S, Cheung AT, Jialal I, Griffen SC, Nguyen D, Glaser N, Aoki T: Evidence of increased inflammation and microcirculatory abnormalities in patients with type 1 diabetes and their role in microvascular complications. Diabetes 2007, 56:2790-2796.
• [12]Pickup JC: Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004, 27:813-823.
• [13]Iwata H, Soga Y, Meguro M, Yoshizawa S, Okada Y, Iwamoto Y, Yamashita A, Takashiba S, Nishimura F: High glucose up-regulates lipopolysaccharide-stimulated inflammatory cytokine production via c-jun N-terminal kinase in the monocytic cell line THP-1. J Endotoxin Res 2007, 13:227-234.
• [14]Wuensch T, Thilo F, Krueger K, Scholze A, Ristow M, Tepel M: High glucose-induced oxidative stress increases transient receptor potential channel expression in human monocytes. Diabetes 2010, 59:844-849.
• [15]Shanmugam N, Reddy MA, Guha M, Natarajan R: High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 2003, 52:1256-1264.
• [16]Morohoshi M, Fujisawa K, Uchimura I, Numano F: The effect of glucose and advanced glycosylation end products on IL-6 production by human monocytes. Ann N Y AcadSci 1995, 748:562-570.
• [17]Ichikawa K, Yoshinari M, Iwase M, Wakisaka M, Doi Y, Iino K, Yamamoto M, Fujishima M: Advanced glycosylation end products induced tissue factor expression in human monocyte-like U937 cells and increased tissue factor expression in monocytes from diabetic patients. Atherosclerosis 1998, 136:281-287.
• [18]Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al.: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000, 404:787-790.
• [19]Orie NN, Zidek W, Tepel M: Increased intracellular generation of reactive oxygen species in mononuclear leukocytes from patients with diabetes mellitus type 2. Exp Clin Endocrinol Diabetes 2000, 108:175-180.
• [20]Devaraj S, Venugopal SK, Singh U, Jialal I: Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}. Diabetes 2005, 54:85-91.
• [21]Nakamura Y, Noma M, Kidokoro M, Kobayashi N, Takei M, Kurashima S, Mukaiyama T, Kato S: Expression of CD33 antigen on normal human activated T lymphocytes. Blood 1994, 83:1442-1443.
• [22]Crocker PR: Siglecs in innate immunity. Curr Opin Pharmacol 2005, 5:431-437.
• [23]Munday J, Floyd H, Crocker PR: Sialic acid binding receptors (siglecs) expressed by macrophages. J Leukoc Biol 1999, 66:705-711.
• [24]Cao H, Crocker PR: Evolution of CD33-related siglecs: regulating host immune functions and escaping pathogen exploitation? Immunology 2011, 132:18-26.
• [25]Avril T, Attrill H, Zhang J, Raper A, Crocker PR: Negative regulation of leucocyte functions by CD33-related siglecs. Biochem Soc Trans 2006, 34:1024-1027.
• [26]Orr SJ, Morgan NM, Elliott J, Burrows JF, Scott CJ, McVicar DW, Johnston JA: CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover. Blood 2007, 109:1061-1068.
• [27]Lajaunias F, Dayer JM, Chizzolini C: Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur J Immunol 2005, 35:243-251.
• [28]Shamsasenjan K, Otsuyama K, Abroun S, Iqbal MS, Mahmoud MS, Asaoku H, Kawano MM: IL-6-induced activation of MYC is responsible for the down-regulation of CD33 expression in CD33+ myeloma cells. Int J Hematol 2009, 89:310-318.
• [29]Wu JH, Ward NC, Indrawan AP, Almeida CA, Hodgson JM, Proudfoot JM, Puddey IB, Croft KD: Effects of alpha-tocopherol and mixed tocopherol supplementation on markers of oxidative stress and inflammation in type 2 diabetes. Clin Chem 2007, 53:511-519.
• [30]Muller T, Grandbarbe L, Morga E, Heuschling P, Luu B: Tocopherol long chain fatty alcohols decrease the production of TNF-alpha and NO radicals by activated microglial cells. Bioorg Med Chem Lett 2004, 14:6023-6026.
• [31]Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, Viswanathan P, Chaudhuri A, Dandona P: Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care 2010, 33:991-997.
• [32]Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, Mohanty P, Dandona P: Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Am J Clin Nutr 2010, 91:940-949.
• [33]Lee JH, Lee W, Kwon OH, Kim JH, Kwon OW, Kim KH, Lim JB: Cytokine profile of peripheral blood in type 2 diabetes mellitus patients with diabetic retinopathy. Ann Clin Lab Sci 2008, 38:361-367.
• [34]Dasu MR, Devaraj S, Jialal I: High glucose induces IL-1beta expression in human monocytes: mechanistic insights. Am J Physiol Endocrinol Metab 2007, 293:E337-E346.
• [35]Hill JR, Kwon G, Marshall CA, McDaniel ML: Hyperglycemic levels of glucose inhibit interleukin 1 release from RAW 264.7 murine macrophages by activation of protein kinase C. J Biol Chem 1998, 273:3308-3313.
• [36]Otto NM, Schindler R, Lun A, Boenisch O, Frei U, Oppert M: Hyperosmotic stress enhances cytokine production and decreases phagocytosis in vitro. Crit Care 2008, 12:R107. BioMed Central Full Text
• [37]Hancu N, Netea MG, Baciu I: High glucose concentrations increase the tumor necrosis factor-alpha production capacity by human peripheral blood mononuclear cells. Rom J Physiol 1998, 35:325-330.
• [38]Corrales JJ, Almeida M, Burgo RM, Hernandez P, Miralles JM, Orfao A: Decreased production of inflammatory cytokines by circulating monocytes and dendritic cells in type 2 diabetic men with atherosclerotic complications. J Diabetes Complications 2007, 21:41-49.
• [39]Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, Dandona P: Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 2009, 32:2281-2287.
• [40]Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E: SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 2001, 276:47944-47949.
• [41]Ehlting C, Lai WS, Schaper F, Brenndorfer ED, Matthes RJ, Heinrich PC, Ludwig S, Blackshear PJ, Gaestel M, Haussinger D, Bode JG: Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-alpha involves activation of the MKK6/p38MAPK/MK2 cascade. J Immunol 2007, 178:2813-2826.
• [42]American Diabetes A: Diagnosis and classification of diabetes mellitus. Diabetes Care 2011, 34:S62-S69. Suppl 1
• [43]Boyum A: Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol 1976, Suppl 5:9-15.
• [44]Denizot F, Lang R: Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 1986, 89:271-277.