Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis

in Journal of Molecular Endocrinology
View More View Less
  • 1 Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea
  • 2 Department of Endocrinology, Severance Hospital, Yonsei University of Medicine, Seoul, Korea

Correspondence should be addressed to J S Yoon: yoonjs@yuhs.ac
Restricted access

Inflammation and adipogenesis represent the main pathogenic mechanisms of Graves’ orbitopathy (GO), and oxidative stress is a well-known inducer of GO pathology. Endoplasmic reticulum (ER) stress has been suggested as a major contributor to inflammation and reactive oxygen species (ROS) generation. In this study, we investigated the role of the ER-stress chaperone protein, binding immunoglobulin protein (BiP), in GO pathogenesis. Using primary cultures of orbital fibroblasts from patients with GO, we examined the role of BiP in GO pathogenesis by silencing its expression with small-interfering RNA (siRNA). Inflammatory cytokine expression was analysed by Western blotting and ELISA. Intracellular ROS levels induced by hydrogen peroxide or cigarette smoke extract were measured by 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. After adipogenic differentiation in BiP siRNA-transfected cells, the cells were stained with Oil Red O, and the levels of adipogenic transcription factors were determined by Western blot analysis. BiP mRNA expression levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. Silencing BiP attenuated the expression of pro-inflammatory cytokines (interleukin-6, intercellular adhesion molecule-1, and monocyte chemotactic protein-1) in primary cultured GO orbital fibroblasts. Silencing BiP also reduced ROS generation, hyaluronan production, and adipocyte differentiation. These findings suggest that ER stress is involved in the aetiology of GO and that modulation of ER stress has therapeutic potential for GO.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 192 192 192
Full Text Views 57 57 57
PDF Downloads 22 22 22
  • Bahn RS 2010 Graves’ ophthalmopathy. New England Journal of Medicine 362 726738. (https://doi.org/10.1056/NEJMra0905750)

  • Barrera MJ, Aguilera S, Castro I, Gonzalez S, Carvajal P, Molina C, Hermoso MA & Gonzalez MJ 2018 Endoplasmic reticulum stress in autoimmune diseases: can altered protein quality control and/or unfolded protein response contribute to autoimmunity? A critical review on Sjogren’s syndrome. Autoimmunity Reviews 17 796808. (https://doi.org/10.1016/j.autrev.2018.02.009)

    • Search Google Scholar
    • Export Citation
  • Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K & Boschi A et al. 2008 Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 18 333346. (https://doi.org/10.1089/thy.2007.0315)

    • Search Google Scholar
    • Export Citation
  • Bertolotti A, Zhang Y, Hendershot LM, Harding HP & Ron D 2000 Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biology 2 326332. (https://doi.org/10.1038/35014014)

    • Search Google Scholar
    • Export Citation
  • Blass S, Union A, Raymackers J, Schumann F, Ungethum U, Muller-Steinbach S, De Keyser F, Engel JM & Burmester GR 2001 The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis and Rheumatism 44 761771. (https://doi.org/10.1002/1529-0131(200104)44:4<761::AID-ANR132>3.0.CO;2-S)

    • Search Google Scholar
    • Export Citation
  • Bothun ED, Scheurer RA, Harrison AR & Lee MS 2009 Update on thyroid eye disease and management. Clinical Ophthalmology 3 543551. (https://doi.org/10.2147/opth.s5228)

    • Search Google Scholar
    • Export Citation
  • Byun JW, Hwang S, Kang CW, Kim JH, Chae MK, Yoon JS & Lee EJ 2016 Therapeutic effect of protocatechuic aldehyde in an in vitro model of graves’ orbitopathy. Investigative Ophthalmology and Visual Science 57 40554062. (https://doi.org/10.1167/iovs.15-19037)

    • Search Google Scholar
    • Export Citation
  • Chong WC, Shastri MD & Eri R 2017 Endoplasmic reticulum stress and oxidative stress: a vicious nexus implicated in bowel disease pathophysiology. International Journal of Molecular Sciences 18 771. (https://doi.org/10.3390/ijms18040771)

    • Search Google Scholar
    • Export Citation
  • Corrigall VM, Bodman-Smith MD, Fife MS, Canas B, Myers LK, Wooley P, Soh C, Staines NA, Pappin DJ & Berlo SE et al. 2001 The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. Journal of Immunology 166 14921498. (https://doi.org/10.4049/jimmunol.166.3.1492)

    • Search Google Scholar
    • Export Citation
  • Dandekar A, Mendez R & Zhang K 2015 Cross talk between ER stress, oxidative stress, and inflammation in health and disease. Methods in Molecular Biology 1292 205214. (https://doi.org/10.1007/978-1-4939-2522-3_15)

    • Search Google Scholar
    • Export Citation
  • Douglas RS, Mester T, Ginter A & Kim DS 2014 Thyrotropin receptor and CD40 mediate interleukin-8 expression in fibrocytes: implications for thyroid-associated ophthalmopathy (an American Ophthalmological Society thesis). Transactions of the American Ophthalmological Society 112 2637.

    • Search Google Scholar
    • Export Citation
  • Flamment M, Hajduch E, Ferre P & Foufelle F 2012 New insights into ER stress-induced insulin resistance. Trends in Endocrinology and Metabolism 23 381390. (https://doi.org/10.1016/j.tem.2012.06.003)

    • Search Google Scholar
    • Export Citation
  • Garrity JA & Bahn RS 2006 Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment. American Journal of Ophthalmology 142 147153. (https://doi.org/10.1016/j.ajo.2006.02.047)

    • Search Google Scholar
    • Export Citation
  • Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M & Ron D 2000 Regulated translation initiation controls stress-induced gene expression in mammalian cells. Molecular Cell 6 10991108. (https://doi.org/10.1016/s1097-2765(0000108-8)

    • Search Google Scholar
    • Export Citation
  • Hondur A, Konuk O, Dincel AS, Bilgihan A, Unal M & Hasanreisoglu B 2008 Oxidative stress and antioxidant activity in orbital fibroadipose tissue in Graves’ ophthalmopathy. Current Eye Research 33 421427. (https://doi.org/10.1080/02713680802123532)

    • Search Google Scholar
    • Export Citation
  • Hotamisligil GS 2010 Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140 900917. (https://doi.org/10.1016/j.cell.2010.02.034)

    • Search Google Scholar
    • Export Citation
  • Kaufman RJ 1999 Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes and Development 13 12111233. (https://doi.org/10.1101/gad.13.10.1211)

    • Search Google Scholar
    • Export Citation
  • Khong JJ, McNab AA, Ebeling PR, Craig JE & Selva D 2016 Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. British Journal of Ophthalmology 100 142150. (https://doi.org/10.1136/bjophthalmol-2015-307399)

    • Search Google Scholar
    • Export Citation
  • Kim I, Xu W & Reed JC 2008 Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nature Reviews: Drug Discovery 7 10131030. (https://doi.org/10.1038/nrd2755)

    • Search Google Scholar
    • Export Citation
  • Kim CY, Lee HJ, Chae MK, Byun JW, Lee EJ & Yoon JS 2015 Therapeutic effect of resveratrol on oxidative stress in graves’ orbitopathy orbital fibroblasts. Investigative Ophthalmology and Visual Science 56 63526361. (https://doi.org/10.1167/iovs.15-16870)

    • Search Google Scholar
    • Export Citation
  • Kim SE, Lee JH, Chae MK, Lee EJ & Yoon JS 2016 The role of sphingosine-1-phosphate in adipogenesis of graves’ orbitopathy. Investigative Ophthalmology and Visual Science 57 301311. (https://doi.org/10.1167/iovs.15-17863)

    • Search Google Scholar
    • Export Citation
  • Ko J, Chae MK, Lee JH, Lee EJ & Yoon JS 2017 Sphingosine-1-phosphate mediates fibrosis in orbital fibroblasts in graves’ orbitopathy. Investigative Ophthalmology and Visual Science 58 25442553. (https://doi.org/10.1167/iovs.16-20684)

    • Search Google Scholar
    • Export Citation
  • Ko J, Kim JY, Lee EJ & Yoon JS 2018 Inhibitory effect of idelalisib, a selective phosphatidylinositol 3-kinase delta inhibitor, on adipogenesis in an in vitro model of Graves’ orbitopathy. Investigative Ophthalmology and Visual Science 59 44774485. (https://doi.org/10.1167/iovs.18-24509)

    • Search Google Scholar
    • Export Citation
  • Ko J, Kim JY, Kim JW & Yoon JS 2020 Anti-oxidative and anti-adipogenic effects of caffeine in an in vitro model of Graves’ orbitopathy. Endocrine Journal 67 439447. (https://doi.org/10.1507/endocrj.EJ19-0521)

    • Search Google Scholar
    • Export Citation
  • Lee WS, Sung MS, Lee EG, Yoo HG, Cheon YH, Chae HJ & Yoo WH 2015 A pathogenic role for ER stress-induced autophagy and ER chaperone GRP78/BiP in T lymphocyte systemic lupus erythematosus. Journal of Leukocyte Biology 97 425433. (https://doi.org/10.1189/jlb.6A0214-097R)

    • Search Google Scholar
    • Export Citation
  • Lee JS, Kim J, Lee EJ & Yoon JS 2019 Therapeutic effect of curcumin, a plant polyphenol extracted from curcuma longae, in fibroblasts from patients with Graves’ orbitopathy. Investigative Ophthalmology and Visual Science 60 41294140. (https://doi.org/10.1167/iovs.19-27376)

    • Search Google Scholar
    • Export Citation
  • Lightfoot AP, Nagaraju K, McArdle A & Cooper RG 2015 Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies – potential role of ER stress pathways. Current Opinion in Rheumatology 27 580585. (https://doi.org/10.1097/BOR.0000000000000212)

    • Search Google Scholar
    • Export Citation
  • Maiuri MC, Zalckvar E, Kimchi A & Kroemer G 2007 Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Reviews: Molecular Cell Biology 8 741752. (https://doi.org/10.1038/nrm2239)

    • Search Google Scholar
    • Export Citation
  • Malhotra JD & Kaufman RJ 2007 Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxidants and Redox Signaling 9 22772293. (https://doi.org/10.1089/ars.2007.1782)

    • Search Google Scholar
    • Export Citation
  • Meng S, Zhang W, Guan LJ, Muhali FS, Zhou JZ, Song RH, Xu J & Zhang JA 2017 Proteomic analysis reveals aberrant expression of CALR and HSPA5 in thyroid tissues of Graves’ disease. Clinical Biochemistry 50 4045. (https://doi.org/10.1016/j.clinbiochem.2016.08.014)

    • Search Google Scholar
    • Export Citation
  • Park YJ, Yoo SA & Kim WU 2014 Role of endoplasmic reticulum stress in rheumatoid arthritis pathogenesis. Journal of Korean Medical Science 29 211. (https://doi.org/10.3346/jkms.2014.29.1.2)

    • Search Google Scholar
    • Export Citation
  • Prattes S, Horl G, Hammer A, Blaschitz A, Graier WF, Sattler W, Zechner R & Steyrer E 2000 Intracellular distribution and mobilization of unesterified cholesterol in adipocytes: triglyceride droplets are surrounded by cholesterol-rich ER-like surface layer structures. Journal of Cell Science 113 29772989.

    • Search Google Scholar
    • Export Citation
  • Ron D & Walter P 2007 Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews: Molecular Cell Biology 8 519529. (https://doi.org/10.1038/nrm2199)

    • Search Google Scholar
    • Export Citation
  • Todd DJ, Lee AH & Glimcher LH 2008 The endoplasmic reticulum stress response in immunity and autoimmunity. Nature Reviews: Immunology 8 663674. (https://doi.org/10.1038/nri2359)

    • Search Google Scholar
    • Export Citation
  • Tu BP & Weissman JS 2004 Oxidative protein folding in eukaryotes: mechanisms and consequences. Journal of Cell Biology 164 341346. (https://doi.org/10.1083/jcb.200311055)

    • Search Google Scholar
    • Export Citation
  • Ulianich L, Terrazzano G, Annunziatella M, Ruggiero G, Beguinot F & Di Jeso B 2011 ER stress impairs MHC class I surface expression and increases susceptibility of thyroid cells to NK-mediated cytotoxicity. Biochimica et Biophysica Acta 1812 431438. (https://doi.org/10.1016/j.bbadis.2010.12.013)

    • Search Google Scholar
    • Export Citation
  • Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM & Prummel MF 2003 TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients. Clinical Endocrinology 58 280287. (https://doi.org/10.1046/j.1365-2265.2003.01708.x)

    • Search Google Scholar
    • Export Citation
  • Woodward AM, Di Zazzo A, Bonini S & Argueso P 2020 Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface. Scientific Reports 10 2216. (https://doi.org/10.1038/s41598-020-59237-3)

    • Search Google Scholar
    • Export Citation
  • Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T & Tohyama M 2001 Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. Journal of Biological Chemistry 276 1393513940. (https://doi.org/10.1074/jbc.M010677200)

    • Search Google Scholar
    • Export Citation
  • Yoon JS, Chae MK, Jang SY, Lee SY & Lee EJ 2012 Antifibrotic effects of quercetin in primary orbital fibroblasts and orbital fat tissue cultures of Graves’ orbitopathy. Investigative Ophthalmology and Visual Science 53 59215929. (https://doi.org/10.1167/iovs.12-9646)

    • Search Google Scholar
    • Export Citation
  • Yoon JS, Lee HJ, Chae MK, Lee SY & Lee EJ 2013 Cigarette smoke extract-induced adipogenesis in Graves’ orbital fibroblasts is inhibited by quercetin via reduction in oxidative stress. Journal of Endocrinology 216 145156. (https://doi.org/10.1530/JOE-12-0257)

    • Search Google Scholar
    • Export Citation
  • Zha BS & Zhou H 2012 ER stress and lipid metabolism in adipocytes. Biochemistry Research International 2012 312943. (https://doi.org/10.1155/2012/312943)

    • Search Google Scholar
    • Export Citation
  • Zhu G, Ye R, Jung DY, Barron E, Friedline RH, Benoit VM, Hinton DR, Kim JK & Lee AS 2013 GRP78 plays an essential role in adipogenesis and postnatal growth in mice. FASEB Journal 27 955964. (https://doi.org/10.1096/fj.12-213330)

    • Search Google Scholar
    • Export Citation