Statins Decrease the Aberrant HLA-DR Expression on Thyrocytes from Patients with Hashimoto's Thyroiditis

Abstract

Statins have been found to exert anti-inflammatory and immune modulatory effects. It seems likely that these drugs may improve thyroid function in patients with Hashimoto's thyroiditis (HT). The objective of our study was to investigate the effect of statins on HLA-DR (human leukocyte antigen D-related) expression of thyrocytes from patients with HT hypothyroidism. Thyroid tissues were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of IFN-γ (50 ng/ml) with or without statins (simvastatin 10 μM or atorvastatin 10 μM) for 72 hours. HLA-DR expression was detected by flow cytometry. Normal thyrocytes were used for controls. HLA-DR expression of HT thyrocytes was much higher than that of normal thyrocytes (41.2±4.5% vs. 2.7±2.1%, p<0.01), which could be further increased by IFN-γ stimulation in both groups (p<0.01). However, simvastatin and atorvastatin could significantly inhibit the “aberrant” HLA-DR expression on HT thyrocytes and decrease IFN-γ- induced HLA-DR expression in both HT and normal thyroid cells (p<0.01). Statins can repress HLA-DR expression of HT thyrocytes, which might inhibit the subsequent lymphocyte activation and ameliorate the immune disturbance of HT.

Key words

statin - Hashimoto's thyroiditis - HLA-DR - atorvastatin - simvastatin

References

• 1 Weetman AP, MacGregor AM. Autoimmune thyroid disease: developments in our understanding.  Endocr Rev. 1994;  15 788-802
• 2 Chistiakov DA. Immunogenetics of Hashimoto's thyroiditis.  J Autoimmun Dis. 2005;  2 1-21
• 3 Kabel PJ, Voorbij HA, Haan M de, Gaag RD van der, Drexhage HA. Intarthyroidal dendritic cells.  J Clin Endocrinol Metab. 1988;  66 199-207
• 4 Many MC, Maniratunga S, Varis I, Dardenne M, Draxhage HA, Denef JF. Two-step development of a Hashimoto-like thyroiditis in genetically autoimmune prone non-obese diabetic (NOD) mice. Effects of iodine-induced cell necrosis.  J Endocrinol. 1995;  147 311-320
• 5 Aichinger G, Fill H, Wick G. In situ immune complexes, lymphocyte subpopulations, and HLA-DR-positive epithelial cells in Hashimoto thyroiditis.  Lab Invest. 1985;  52 132-140
• 6 Iwatani Y, Gerstein HC, Iitaka M, Row VV, Volpe R. Thyrocyte HLA-DR expression and interferon-gamma production in autoimmune thyroid disease.  J Clin Endocrinol Metab. 1986;  63 695-708
• 7 Bottazzo GF, Pujol-Borell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity.  Lancet. 1983;  2 1115-1118
• 8 Rapoport B, MacLachlan SM. Thyroid autoimmunity.  J Clin Invest. 2001;  108 1253-1259
• 9 Raggatt LJ, Partridge NC. HMG-CoA reductase inhibitors as immunomodulators.  Drug. 2002;  62 2185-2191
• 10 Bocan TM. Pleiotropic effects of HMG-CoA reductase inhibitors.  Current Opinion in Investigational Drugs. 2002;  3 1312-1317
• 11 Shovman O, Levy Y, Gilburd B, Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins.  Immunol Res. 2002;  25 271-285
• 12 Mach F. Statins as immunomodulators.  Transplant Immunol. 2002;  9 197-200
• 13 Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona M, Vecchi A, Pinza M, Mantovani A. Inhibition of monocyte chemotactic protein-1 synthesis by statins.  Lab Invest. 2000;  80 1095-1100
• 14 Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro.  Immunopharmacology. 1996;  34 51-61
• 15 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator.  Nat Med. 2000;  6 1399-1402
• 16 Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi JD, Kawata N, Hage A, Drinkwater DC, Stevenson LW. Effect of pravastatin on outcomes after cardiac transplantation.  N Engl J Med. 1995;  333 621-627
• 17 Johnson BA, Iacono AT, Zeevi A, MacCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts.  Am J Resp Crit Care Med. 2003;  167 1271-1278
• 18 Leung BP, Sattar N, Crilly A, Prach M, MacCarey DW, Payne H, Madhok R, Campbell C, Gracie JA, Liew FY, MacInnes IB. Novel anti-inflammatory role for simvastatin in inflammatory arthritis.  J Immunol. 2003;  170 1524-1530
• 19 Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.  Nature. 2002;  420 78-84
• 20 Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I. Oral simvastatin treatment in relapsing-remitting multiple sclerosis.  Lancet. 2004;  363 1607-1608
• 21 MacCarey DW, MacInnes IB, Madhok R, Hampson R, Scherbakova O, Ford I, Capell HA, Sattar N. Trial of atorvastatin in rheumatoid arthritis (TARA): a double-blind randomised placebo-controlled trial.  Lancet. 2004;  363 2015-2021
• 22 Gullu S, Emral R, Bastemir M, Parkes AB, Lazarus JH. In vivo and in vitro effects of statins on lymphocytes in patients with Hashimoto's thyroiditis.  Eur J Endocrinol. 2005;  153 41-48
• 23 Wu XH, Liu CP, Qin YW, Liu C. Effects of statins in the treatment of subclinical hypothyroidsm patients with Hashimoto thyroiditis: a preliminary study.  Thyroid. 2005;  15 ((Suppl 1)) S168
• 24 Kwak B, Mulhaupt F, Veillard N, Pelli G, Mach F. The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells.  Swiss Med Wkly. 2001;  131 41-46
• 25 Sadeghi MM, Tiglio A, Sadigh K, O’Donnell L, Collinge M, Pardi R, Bender JR. Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductase inhibitors.  Transplantation. 2001;  71 1262-1268
• 26 Guo J, Wang Y, Rapoport B, MacLachlan SM. Evidence for antigen presentation to sensitized T cells by thyroid peroxidase (TPO)-specific B cells in mice injected with fibroblasts co-expressing TPO and MHC class II.  Clin Exp Immunol. 2000;  119 38-46
• 27 Li YS, Kanamoto N, Hataya Y, Moriyama K, Hiratani H, Nakao K, Akamizu T. Transgenic mice producing major histocompatibility complex class II molecules on thyroid cells do not develop ap-parent autoimmune thyroid diseases.  Endocrinology. 2004;  145 2524-2530
• 28 Kimura H, Kimura M, Tzou SC, Chen YC, Suzuki K, Rose NR, Caturegli P. Expression of class II major histocompatibility complex molecules on thyrocytes does not cause spontaneous thyroiditis but mildly increases its severity after immunization.  Endocrinology. 2005;  146 1154-1162
• 29 Kimura1 H, Caturegli P. Chemokine orchestration of autoimmune thyroiditis.  Thyroid. 2007;  17 1005-1010
• 30 Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases.  Endocr Rev. 2007;  28 492-520
• 31 Ushioda M, Makita K, Takamatsu K, Horiguchi F, Aoki D. Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women.  Horm Metab Res. 2006;  38 581-586

1 Both authors contributed equally to this article.

Correspondence