Decreased expression levels of Nurr1 are associated with chronic inflammation in patients with type 2 diabetes

Xu,Ying; Huang,Qi; Zhang,Wenfang; Wang,Yaping; Zeng,Qingling; He,Chunyan; Xue,Junli; Chen,Jin; Hu,Xuemei; Xu,Yancheng

doi:10.3892/mmr.2015.4105

Decreased expression levels of Nurr1 are associated with chronic inflammation in patients with type 2 diabetes

Authors:
- Ying Xu
- Qi Huang
- Wenfang Zhang
- Yaping Wang
- Qingling Zeng
- Chunyan He
- Junli Xue
- Jin Chen
- Xuemei Hu
- Yancheng Xu
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Affiliations: Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Endocrinology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430071, P.R. China
Published online on: July 21, 2015 https://doi.org/10.3892/mmr.2015.4105
Pages: 5487-5493

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Abstract

Chronic inflammation is associated with insulin resistance, a characteristic of type 2 diabetes (T2D). Nuclear receptor‑related protein 1 (Nurr1) can regulate inflammation, dependent on the nature of individual diseases. However, whether Nurr1 regulates chronic inflammation during the pathogenic process of T2D in humans remains to be fully elucidated. The present study aimed to investigate the potential association between the expression of Nurr1 in peripheral blood mononuclear cells (PBMCs) and inflammation in patients with T2D. The levels of plasma tumor necrosis factor (TNF)α and interleukin (IL)‑6, the relative expression levels of Nurr1, and glycogen synthase kinase (GSK)‑3β phosphorylation in PBMCs from 40 patients with T2D and 40 healthy controls (HC group) were examined, and their potential association with clinical measures were analyzed. The expression levels of Nurr1, induced by high glucose and palmitic acid, were assessed in the PBMCs from the HC group. Compared with the HC group, significantly higher levels of plasma TNFα and IL‑6 were correlated positively with the degree of insulin resistance in the T2D patients. However, significantly lower expression levels of Nurr1 and GSK‑3β phosphorylation in the PBMCs were correlated negatively with the levels of TNFα, IL‑6, fasting insulin and insulin resistance in the T2D patients. Treatment of the PBMCs with high glucose or palmitic acid inhibited the expression of Nurr1 in a dose‑ and time‑dependent manner. Therefore, decreased expression levels of Nurr1 were associated with chronic inflammation and insulin resistance in patients with T2D.

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1	Tuomi T, Santoro N, Caprio S, Cai M, Weng J and Groop L: The many faces of diabetes: a disease with increasing heterogeneity. Lancet. 383:1084–1094. 2014. View Article : Google Scholar
2	Ma RC and Chan JC: Type 2 diabetes in east Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci. 1281:64–91. 2013. View Article : Google Scholar : PubMed/NCBI
3	Cildir G, Akincilar SC and Tergaonkar V: Chronic adipose tissue inflammation: all immune cells on the stage. Trends Mol Med. 19:487–500. 2013. View Article : Google Scholar : PubMed/NCBI
4	Tilg H and Moschen AR: Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 14:222–231. 2008. View Article : Google Scholar : PubMed/NCBI
5	Osborn O and Olefsky JM: The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 18:363–374. 2012. View Article : Google Scholar : PubMed/NCBI
6	Feuerer M, Herrero L, Cipolletta D, et al: Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 15:930–939. 2009. View Article : Google Scholar : PubMed/NCBI
7	DeFuria J, Belkina AC, Jagannathan-Bogdan M, et al: B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci USA. 110:5133–5138. 2013. View Article : Google Scholar : PubMed/NCBI
8	Navarro-Gonzalez J, Mora-Fernandez C, Gomez-Chinchon M, Muros M, Herrera H and Garcia J: Serum and gene expression profile of tumor necrosis factor-alpha and interleukin-6 in hypertensive diabetic patients: effect of amlodipine administration. Int J Immunopathol Pharmacol. 23:51–59. 2010.PubMed/NCBI
9	Hamers AA, Hanna RN, Nowyhed H, Hedrick CC and de Vries CJ: NR4A nuclear receptors in immunity and atherosclerosis. Curr Opin Lipidol. 24:381–385. 2013.PubMed/NCBI
10	Pearen MA and Muscat GE: Minireview: Nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol. 24:1891–1903. 2010. View Article : Google Scholar : PubMed/NCBI
11	Fu Y, Luo L, Luo N, Zhu X and Garvey WT: NR4A orphan nuclear receptors modulate insulin action and the glucose transport system: potential role in insulin resistance. J Biol Chem. 282:31525–31533. 2007. View Article : Google Scholar : PubMed/NCBI
12	Bonta PI, Pols TW, van Tiel CM, et al: Nuclear receptor Nurr1 is expressed in and is associated with human restenosis and inhibits vascular lesion formation in mice involving inhibition of smooth muscle cell proliferation and inflammation. Circulation. 121:2023–2032. 2010. View Article : Google Scholar : PubMed/NCBI
13	McEvoy AN, Bresnihan B, Fitzgerald O and Murphy EP: Corticotropin-releasing hormone signaling in synovial tissue vascular endothelium is mediated through the cAMP/CREB pathway. Ann N Y Acad Sci. 966:119–130. 2002. View Article : Google Scholar : PubMed/NCBI
14	Zhang Z, Li X, Xie WJ, et al: Anti-parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's disease. CNS Neurol Disord Drug Targets. 11:768–773. 2012. View Article : Google Scholar : PubMed/NCBI
15	Block Ml, Zecca L and Hong JS: Microglia-mediated neuro-toxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 8:57–69. 2007. View Article : Google Scholar
16	Bonta PI, van Tiel CM, Vos M, et al: Nuclear receptors Nur77, Nurr1 and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses. Arterioscler Thromb Vasc Biol. 26:2288–2294. 2006. View Article : Google Scholar : PubMed/NCBI
17	Wang T, Jiang Q, Chan C, et al: Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR. Blood. 113:2906–2913. 2009. View Article : Google Scholar : PubMed/NCBI
18	Buss H, Dörrie A, Schmitz Ml, et al: Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity. J Biol Chem. 279:49571–49574. 2004. View Article : Google Scholar : PubMed/NCBI
19	Saijo K, Winner B, Carson CT, et al: A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell. 137:47–59. 2009. View Article : Google Scholar : PubMed/NCBI
20	Wan F and Lenardo MJ: The nuclear signaling of NF-kappaB: current knowledge, new insights and future perspectives. Cell Res. 20:24–33. 2010. View Article : Google Scholar
21	McMorrow JP and Murphy EP: Inflammation: a role for NR4A orphan nuclear receptors? Biochem Soc Trans. 39:688–693. 2011. View Article : Google Scholar : PubMed/NCBI
22	O'Kane M, Murphy EP and Kirby B: The role of cortico-tropin-releasing hormone in immune-mediated cutaneous inflammatory disease. Exp Dermatol. 15:143–153. 2006. View Article : Google Scholar : PubMed/NCBI
23	Pei L, Castrillo A, Chen M, Hoffmann A and Tontonoz P: Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J Biol Chem. 280:29256–29262. 2005. View Article : Google Scholar : PubMed/NCBI
24	Safe S, Jin UH, Hedrick E, Reeder A and Lee SO: Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol. 28:157–172. 2014. View Article : Google Scholar :
25	Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 26(Suppl 1): S5–S20. 2003. View Article : Google Scholar
26	Turner RC, Holman RR, Matthews D, Hockaday TD and Peto J: Insulin deficiency and insulin resistance interaction in diabetes: Estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. Metabolism. 28:1086–1096. 1979. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of the relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
28	Hâncu N, Netea MG and Baciu I: High glucose concentrations increase the tumor necrosis factor-alpha production capacity by human peripheral blood mononuclear cells. Rom J Physiol. 35:325–330. 1998.
29	Fogeda M, Gallart L, Gutierrez C, et al: High expression of tumor necrosis factor alpha receptors in peripheral blood mono-nuclear cells of obese type 2 diabetic women. Eur Cytokine Netw. 15:60–66. 2004.PubMed/NCBI
30	Mylona EE, Mouktaroudi M, Crisan TO, et al: Enhanced interleukin-1beta production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res Ther. 14:R1582012. View Article : Google Scholar
31	D'Amore S, Vacca M, Graziano G, et al: Nuclear receptors expression chart in peripheral blood mononuclear cells identifies patients with metabolic syndrome. Biochim Biophys Acta. 1832:2289–2301. 2013. View Article : Google Scholar : PubMed/NCBI
32	Giulietti A, Stoffels K, Decallonne B, Overbergh L and Mathieu C: Monocytic expression behavior of cytokines in diabetic patients upon inflammatory stimulation. Ann N Y Acad Sci. 1037:74–78. 2004. View Article : Google Scholar
33	Davies MR, Harding CJ, Raines S, et al: Nurr1 dependent regulation of pro-inflammatory mediators in immortalised synovial fibroblasts. J Inflamm (Lond). 2:152005. View Article : Google Scholar
34	Lee JK, Tran T and Tansey MG: Neuroinflammation in Parkinson's disease. J Neuroimmune Pharmacol. 4:419–429. 2009. View Article : Google Scholar : PubMed/NCBI