Increased Protein and mRNA Expression of Resistin After Dexamethasone Administration

Abstract

Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.

Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype.

Key words

microarray analysis - gene expression - single nucleotide polymorphism

• References

• 1 McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol 2008; 20: 131-137
• 2 Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 2005; 44: 61-98
• 3 Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O’Shea JJ, Chrousos GP, Bornstein SR. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002; 16: 61-71
• 4 Rulcova A, Krausova L, Smutny T, Vrzal R, Dvorak Z, Jover R, Pavek P. Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alpha upregulation in primary human hepatocytes. Pharmacol Rep 2013; 65: 1322-1335
• 5 Cheng X, Zhao X, Khurana S, Bruggeman LA, Kao HY. Microarray analyses of glucocorticoid and vitamin D3 target genes in differentiating cultured human podocytes. PLoS One 2013; 8: e60213
• 6 Ahlstrom M, Pekkinen M, Lamberg-Allardt C. Dexamethasone downregulates the expression of parathyroid hormone-related protein (PTHrP) in mesenchymal stem cells. Steroids 2009; 74: 277-282
• 7 Menke A, Arloth J, Putz B, Weber P, Klengel T, Mehta D, Gonik M, Rex-Haffner M, Rubel J, Uhr M, Lucae S, Deussing JM, Muller-Myhsok B, Holsboer F, Binder EB. Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients. Neuropsychopharmacology 2012; 37: 1455-1464
• 8 Sasayama D, Hori H, Nakamura S, Miyata R, Teraishi T, Hattori K, Ota M, Yamamoto N, Higuchi T, Amano N, Kunugi H. Identification of single nucleotide polymorphisms regulating peripheral blood mRNA expression with genome-wide significance: an eQTL study in the Japanese population. PLoS One 2013; 8: e54967
• 9 Onuma H, Tabara Y, Kawamura R, Tanaka T, Ohashi J, Nishida W, Takata Y, Ochi M, Yamada K, Kawamoto R, Kohara K, Miki T, Makino H, Osawa H. A at single nucleotide polymorphism-358 is required for G at -420 to confer the highest plasma resistin in the general Japanese population. PLoS One 2010; 5: e9718
• 10 Sasayama D, Hori H, Yamamoto N, Nakamura S, Teraishi T, Tatsumi M, Hattori K, Ota M, Higuchi T, Kunugi H. ITIH3 polymorphism may confer susceptibility to psychiatric disorders by altering the expression levels of GLT8D1. J Psychiatr Res 2014; 50: 79-83
• 11 Tanaka N, Kusunoki N, Kusunoki Y, Hasunuma T, Kawai S. Resistin is associated with the inflammation process in patients with systemic autoimmune diseases undergoing glucocorticoid therapy: comparison with leptin and adiponectin. Mod Rheumatol 2013; 23: 8-18
• 12 Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med 2004; 1: e45
• 13 Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 2003; 309: 286-290
• 14 Schuld A, Kraus T, Haack M, Hinze-Selch D, Zobel AW, Holsboer F, Pollmacher T. Effects of dexamethasone on cytokine plasma levels and white blood cell counts in depressed patients. Psychoneuroendocrinology 2001; 26: 65-76
• 15 Tsiotra PC, Boutati E, Dimitriadis G, Raptis SA. High insulin and leptin increase resistin and inflammatory cytokine production from human mononuclear cells. Biomed Res Int 2013; 2013: 487081
• 16 Lewandowski KC, Szosland K, Lewinski A. Short-term dexamethasone administration does not alter serum adiponectin or resistin concentrations in overweight and obese subjects despite an increase in insulin resistance. Clin Endocrinol (Oxf) 2006; 65: 551-552
• 17 Raff H, Bruder ED. Adiponectin and resistin in the neonatal rat: effects of dexamethasone and hypoxia. Endocrine 2006; 29: 341-344
• 18 Weber-Hamann B, Kratzsch J, Kopf D, Lederbogen F, Gilles M, Heuser I, Deuschle M. Resistin and adiponectin in major depression: the association with free cortisol and effects of antidepressant treatment. J Psychiatr Res 2007; 41: 344-350
• 19 Tokuyama Y, Osawa H, Ishizuka T, Onuma H, Matsui K, Egashira T, Makino H, Kanatsuka A. Serum resistin level is associated with insulin sensitivity in Japanese patients with type 2 diabetes mellitus. Metabolism 2007; 56: 693-698
• 20 Seo JB, Noh MJ, Yoo EJ, Park SY, Park J, Lee IK, Park SD, Kim JB. Functional characterization of the human resistin promoter with adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element binding protein 1c and CCAAT enhancer binding protein-alpha. Mol Endocrinol 2003; 17: 1522-1533
• 21 Gertz EM, Sengupta K, Difilippantonio MJ, Ried T, Schaffer AA. Evaluating annotations of an Agilent expression chip suggests that many features cannot be interpreted. BMC Genomics 2009; 10: 566