Increased expression of the interleukin-1 receptor-associated kinase (IRAK)-1 is associated with adipose tissue inflammatory state in obesity

Diabetology & Metabolic Syndrome

Kazem Behbehani¹  Sardar Sindhu¹  Amal Hasan¹  Munera Alghanim¹  Reeby Thomas¹  Puthiyaveetil Kochumon Shihab¹  Rasheed Ahmad¹ 

[1] Laboratory of Immunology & Innovative Cell Therapy, Dasman Diabetes Institute (DDI), Dasman, Kuwait City, 15462, Kuwait

关键词: TLR/IL-1R/MyD88 pathway;    Meta-inflammation;    Metabolic inflammation;    Type-2 diabetes;    Obesity;    Adipose tissue;    Adapter protein;    Interleukin-1 receptor-associated kinase;   

Others  :  1225022
DOI  :  10.1186/s13098-015-0067-7

 received in 2015-02-25, accepted in 2015-08-18,  发布年份 2015

【 摘 要 】

Background

The emerging role of TLR2/4 as immuno-metabolic receptors points to key involvement of TLR/IL-1R/MyD88 pathway in obesity/type-2 diabetes (T2D). IL1R-associated kinase (IRAK)-1 is a critical adapter protein (serine/threonine kinase) of this signaling pathway. The changes in adipose tissue expression of IRAK-1 in obesity/T2D remain unclear. We determined modulations in IRAK-1 gene/protein expression in the subcutaneous adipose tissues from lean, overweight and obese individuals with or without T2D.

Methods

A total of 49 non-diabetic (22 obese, 19 overweight and 8 lean) and 42 T2D (31 obese, 9 overweight and 2 lean) adipose tissue samples were obtained by abdominal subcutaneous fat pad biopsy and IRAK-1 expression was determined using real-time RT-PCR, immunohistochemistry, and confocal microscopy. IRAK-1 mRNA expression was compared with adipose tissue proinflammatory mediators (TNF-α, IL-6, IL-18), macrophage markers (CD68, CD11c, CD163), and plasma markers (CCL-5, C-reactive protein, adiponectin, and triglycerides). The data were analyzed using t test, Pearson’s correlation, and multiple stepwise linear regression test.

Results

In non-diabetics, IRAK-1 gene expression was elevated in obese (P = 0.01) and overweight (P = 0.04) as compared with lean individuals and this increase correlated with body mass index (r = 0.45; P = 0.001) and fat percentage (r = 0.36; P = 0.01). In diabetics, IRAK-1 mRNA expression was also higher in obese as compared with lean subjects (P = 0.012). As also shown by immunohistochemistry/confocal microscopy in non-diabetics and by immunohistochemistry in diabetics, IRAK-1 protein expression was higher in obese than overweight and lean adipose tissues. IRAK-1 gene expression correlated positively/significantly with mRNAs of TNF-α (r = 0.46; P = 0.0008), IL-6 (r = 0.30; P = 0.03) and IL-18 (r = 0.31; P = 0.028) in non-diabetics; and only with TNF-α (r = 0.32; P = 0.03) in diabetics. IRAK-1 expression also correlated positively/significantly with CD68 (r = 0.32; P = 0.02), CD11c (r = 0.30; P = 0.03), and CD163 (r = 0.43; P = 0.001) in non-diabetics; and only with CD163 (r = 0.34; P = 0.02) in diabetics. IRAK-1 mRNA levels also correlated with plasma markers including CCL-5 (r = 0.39; P = 0.02), C-reactive protein (r = 0.48; P = 0.005), adiponectin (r = −0.36; P = 0.04), and triglycerides (r = 0.40; P = 0.02) in non-diabetics; and only with triglycerides (r = −0.36; P = 0.04) in diabetics. IRAK-1 expression related with TLR2 (r = 0.39; P = 0.007) and MyD88 (r = 0.36; P = 0.01) in non-diabetics; and MyD88 (r = 0.52; P = 0.0003) in diabetics.

Conclusions

The elevated IRAK-1 expression in obese adipose tissue showed consensus with local/circulatory inflammatory signatures and represented as a tissue marker for metabolic inflammation. The data have clinical significance as interventions causing IRAK-1 suppression may alleviate meta-inflammation in obesity/T2D.

【 授权许可】

   
2015 Ahmad et al.

【 图 表 】

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【 参考文献 】

• [1]Calder PC, Ahluwalia N, Brouns F, Buetler T, Clement K, Cunningham K, et al.: Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 2011, 106(Suppl 3):S5-S78.
• [2]Dandona P, Aljada A, Bandyopadhyay A: Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004, 25:4-7.
• [3]Khaodhiar L, Ling PR, Blackburn GL, Bistrian BR: Serum levels of interleukin-6 and C-reactive protein correlate with body mass index across the broad range of obesity. JPEN J Parenter Enteral Nutr 2004, 28:410-415.
• [4]Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, et al.: Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol. 2007, 178:1748-1758.
• [5]O’Neill LA: How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol 2006, 18:3-9.
• [6]Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL, et al.: MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 1998, 273:12203-12209.
• [7]Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11:373-384.
• [8]Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al.: Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2000, 2:346-351.
• [9]Huang J, Gao X, Li S, Cao Z: Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein. Proc Natl Acad Sci USA 1997, 94:12829-12832.
• [10]Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X: IRAK-mediated translocation of TRAF6 and TAB 2 in the interleukin-1-induced activation of NFkappa B. J Biol Chem 2001, 276:41661-41667.
• [11]Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, et al.: TAB 2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 2000, 5:649-658.
• [12]Ahmad R, Al-Mass A, Atizado V, Al-Hubail A, Al-Ghimlas F, Al-Arouj M, et al.: Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. J Inflamm (Lond) 2012, 9:48. BioMed Central Full Text
• [13]van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, et al.: Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest. 2013, 123:3395-3403.
• [14]Kanakaraj P, Schafer PH, Cavender DE, Wu Y, Ngo K, Grealish PF, et al.: Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. J Exp Med 1998, 187:2073-2079.
• [15]Thomas JA, Allen JL, Tsen M, Dubnicoff T, Danao J, Liao XC, et al.: Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J Immunol. 1999, 163:978-984.
• [16]Muzio M, Ni J, Feng P, Dixit VM: IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 1997, 278:1612-1615.
• [17]Cao Z, Henzel WJ, Gao X: IRAK. a kinase associated with the interleukin-1 receptor. Science 1996, 271:1128-1131.
• [18]Kanakaraj P, Ngo K, Wu Y, Angulo A, Ghazal P, Harris CA, et al.: Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med 1999, 189:1129-1138.
• [19]Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, et al.: Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 2008, 9:684-691.
• [20]Rakoff-Nahoum S, Medzhitov R: Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 2007, 317:124-127.
• [21]Cataisson C, Salcedo R, Hakim S, Moffitt BA, Wright L, Yi M, et al.: IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. J Exp Med 2012, 209:1689-1702.
• [22]Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R, et al.: MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med 2012, 209:1671-1687.
• [23]Rhyasen GW, Starczynowski DT: IRAK signalling in cancer. Br J Cancer 2015, 112:232-237.
• [24]Wozniak SE, Gee LL, Wachtel MS, Frezza EE: Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009, 54:1847-1856.
• [25]Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, et al.: PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007, 6:137-143.
• [26]Koppaka S, Kehlenbrink S, Carey M, Li W, Sanchez E, Lee DE, et al.: Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans. Diabetes 2013, 62:1843-1854.
• [27]Sutinen EM, Pirttila T, Anderson G, Salminen A, Ojala JO: Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-beta production in human neuron-like cells. J Neuroinflammation. 2012, 9:199. BioMed Central Full Text
• [28]Huang HY, Yu HT, Chan SH, Lee CL, Wang HS, Soong YK: Eutopic endometrial interleukin-18 system mRNA and protein expression at the level of endometrial-myometrial interface in adenomyosis patients. Fertil Steril 2010, 94:33-39.
• [29]Bruun JM, Stallknecht B, Helge JW, Richelsen B: Interleukin-18 in plasma and adipose tissue: effects of obesity, insulin resistance, and weight loss. Eur J Endocrinol 2007, 157:465-471.
• [30]Kobashi C, Asamizu S, Ishiki M, Iwata M, Usui I, Yamazaki K, et al.: Inhibitory effect of IL-8 on insulin action in human adipocytes via MAP kinase pathway. J Inflamm (Lond) 2009, 6:25. BioMed Central Full Text
• [31]Bigornia SJ, Farb MG, Mott MM, Hess DT, Carmine B, Fiscale A, et al.: Relation of depot-specific adipose inflammation to insulin resistance in human obesity. Nutr Diabetes. 2012, 2:e30.
• [32]Alexopoulos N, Katritsis D, Raggi P: Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis 2014, 233:104-112.
• [33]Ohman MK, Shen Y, Obimba CI, Wright AP, Warnock M, et al.: Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008, 117:798-805.
• [34]Samaras K, Botelho NK, Chisholm DJ, Lord RV: Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity (Silver Spring). 2010, 18:884-889.
• [35]Lolmede K, Duffaut C, Zakaroff-Girard A, Bouloumie A: Immune cells in adipose tissue: key players in metabolic disorders. Diabetes Metab. 2011, 37:283-290.
• [36]Morris DL, Singer K, Lumeng CN: Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care. 2011, 14:341-346.
• [37]Sell H, Eckel J: Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes. Curr Opin Clin Nutr Metab Care. 2010, 13:366-370.
• [38]Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003, 112:1796-1808.
• [39]Holness CL, Simmons DL: Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 1993, 81:1607-1613.
• [40]Lecoanet-Henchoz S, Gauchat JF, Aubry JP, Graber P, Life P, Paul-Eugene N, et al.: CD23 regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18. Immunity 1995, 3:119-125.
• [41]Van den Heuvel MM, Tensen CP, van As JH, Van den Berg TK, Fluitsma DM, Dijkstra CD, et al.: Regulation of CD 163 on human macrophages: cross-linking of CD163 induces signaling and activation. J Leukoc Biol 1999, 66:858-866.
• [42]Buechler C, Ritter M, Orso E, Langmann T, Klucken J, Schmitz G: Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 2000, 67:97-103.
• [43]Santander AM, Lopez-Ocejo O, Casas O, Agostini T, Sanchez L, Lamas-Basulto E, et al.: Paracrine interactions between adipocytes and tumor cells recruit and modify macrophages to the mammary tumor microenvironment: the role of obesity and inflammation in breast adipose tissue. Cancers (Basel). 2015, 7:143-178.
• [44]Zhang X, Dang Y, Li P, Rong M, Chen G: Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study. Int J Clin Exp Pathol. 2014, 7:8096-8104.
• [45]Jacob CO, Zhu J, Armstrong DL, Yan M, Han J, Zhou XJ, et al.: Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci USA 2009, 106:6256-6261.
• [46]Sun M, Yang P, Du L, Yang Y, Ye J: The role of interleukin-1 receptor-associated kinases in Vogt-Koyanagi-Harada disease. PLoS One 2014, 9:e93214.
• [47]Cui JG, Li YY, Zhao Y, Bhattacharjee S, Lukiw WJ: Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease. J Biol Chem 2010, 285:38951-38960.
• [48]Weitzenfeld P, Ben-Baruch A: The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett 2014, 352:36-53.
• [49]Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001, 286:327-334.
• [50]Allin KH, Nordestgaard BG: Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci 2011, 48:155-170.
• [51]Lu H, Ouyang W, Huang C: Inflammation, a key event in cancer development. Mol Cancer Res 2006, 4:221-233.
• [52]Baer PC, Gauer S, Wegner B, Schubert R, Geiger H: C-reactive protein induced activation of MAP-K and RANTES in human renal distal tubular epithelial cells in vitro. Clin Nephrol 2006, 66:177-183.
• [53]Ukkola O, Santaniemi M: Adiponectin: a link between excess adiposity and associated comorbidities? J Mol Med (Berl). 2002, 80:696-702.
• [54]Despres JP, Moorjani S, Tremblay A, Ferland M, Lupien PJ, Nadeau A, et al.: Relation of high plasma triglyceride levels associated with obesity and regional adipose tissue distribution to plasma lipoprotein-lipid composition in premenopausal women. Clin Invest Med 1989, 12:374-380.
• [55]Austin MA: Plasma triglyceride as a risk factor for cardiovascular disease. Can J Cardiol. 1998, 14(Suppl B):14B-17B.
• [56]National Cholesterol Education Program: Expert panel on detection and treatment of high blood cholesterol in adults: third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report Circulation. 2002, 106:3143-3421.
• [57]Ospelt C, Gay S: TLRs and chronic inflammation. Int J Biochem Cell Biol 2010, 42:495-505.
• [58]Chun E, Lee SH, Lee SY, Shim EJ, Cho SH, Min KU, et al.: Toll-like receptor expression on peripheral blood mononuclear cells in asthmatics: implications for asthma management. J Clin Immunol 2010, 30:459-464.
• [59]Himmel ME, Hardenberg G, Piccirillo CA, Steiner TS, Levings MK: The role of T-regulatory cells and Toll-like receptors in the pathogenesis of human inflammatory bowel disease. Immunology 2008, 125:145-153.
• [60]Huang QQ, Pope RM: The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep 2009, 11:357-364.
• [61]Devaraj S, Dasu MR, Rockwood J, Winter W, Griffen SC, Jialal I: Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. J Clin Endocrinol Metab 2008, 93:578-583.
• [62]Rajamani U, Jialal I: Hyperglycemia induces Toll-like receptor-2 and -4 expression and activity in human microvascular retinal endothelial cells: implications for diabetic retinopathy. J Diabetes Res. 2014, 2014:790902.
• [63]Kaur H, Chien A, Jialal I: Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am J Physiol Renal Physiol. 2012, 303:F1145-F1150.
• [64]Tencerova M, Kracmerova J, Krauzova E, Malisova L, Kovacova Z, Wedellova Z, et al.: Experimental hyperglycemia induces an increase of monocyte and T-lymphocyte content in adipose tissue of healthy obese women. PLoS One 2015, 10:e0122872.
• [65]Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, et al.: Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 2004, 279:16971-16979.
• [66]Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, et al.: 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.
• [67]Ehses JA, Meier DT, Wueest S, Rytka J, Boller S, Wielinga PY, et al.: Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia 2010, 53:1795-1806.
• [68]Kiura K, Kataoka H, Yasuda M, Inoue N, Shibata K: The diacylated lipopeptide FSL-1 induces TLR2-mediated Th2 responses. FEMS Immunol Med Microbiol 2006, 48:44-55.
• [69]Karumuthil-Melethil S, Perez N, Li R, Vasu C: Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. J Immunol. 2008, 181:8323-8334.