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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Ganglioside GT1b increases hyaluronic acid synthase 2 via PI3K activation with TLR2 dependence in orbital fibroblasts from thyroid eye disease patients

  • Yoo, Hyun Kyu (Department of Ophthalmology, Ajou University School of Medicine) ;
  • Park, Hyunju (Department of Physiology, Inflammation-Cancer Microenvironment Research Center, Ewha Womans University School of Medicine) ;
  • Hwang, Hye Suk (Department of Ophthalmology, Ajou University School of Medicine) ;
  • Kim, Hee Ja (Department of Physiology, Inflammation-Cancer Microenvironment Research Center, Ewha Womans University School of Medicine) ;
  • Choi, Youn-Hee (Department of Physiology, Inflammation-Cancer Microenvironment Research Center, Ewha Womans University School of Medicine) ;
  • Kook, Koung Hoon (Department of Ophthalmology, Ajou University School of Medicine)
  • Received : 2020.08.26
  • Accepted : 2020.12.17
  • Published : 2021.02.28
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Abstract

Thyroid eye disease (TED) is a complex autoimmune disease with a spectrum of signs. we previously reported that trisialoganglioside (GT)1b is significantly overexpressed in the orbital tissue of TED patients, and that exogenous GT1b strongly induced HA synthesis in orbital fibroblasts. However, the signaling pathway in GT1b-induced hyaluronic acid synthase (HAS) expression in orbital fibroblasts from TED patients have rarely been investigated. Here, we demonstrated that GT1b induced phosphorylation of Akt/mTOR in a dose-dependent manner in orbital fibroblasts from TED patients. Both co-treatment with a specific inhibitor for PI3K and siRNA knockdown of TLR2 attenuated GT1b-induced Akt phosphorylation. GT1b significantly induced HAS2 expression at both the transcriptional and translational level, which was suppressed by specific inhibitors of PI3K or Akt/mTOR, and by siRNA knockdown of TLR2. In conclusion, GT1b induced HAS2 in orbital fibroblasts from TED patients via activation of the PI3K-related signaling pathway, dependent on TLR2.

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References

  1. Kazim M, Goldberg RA and Smith TJ (2002) Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy. Arch Ophthalmol 120, 380-386 https://doi.org/10.1001/archopht.120.3.380
  2. Garrity JA and Bahn RS (2006) Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment. Am J Ophthalmol 142, 147-153 https://doi.org/10.1016/j.ajo.2006.02.047
  3. Naik VM, Naik MN, Goldberg RA, Smith TJ and Douglas RS (2010) Immunopathogenesis of thyroid eye disease: emerging paradigms. Surv Ophthalmol 55, 215-226 https://doi.org/10.1016/j.survophthal.2009.06.009
  4. Bahn RS (2010) Graves' ophthalmopathy. N Engl J Med 362, 726-738 https://doi.org/10.1056/NEJMra0905750
  5. Smith TJ, Bahn RS and Gorman CA (1989) Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev 10, 366-391 https://doi.org/10.1210/edrv-10-3-366
  6. Schulz T, Schumacher U and Prehm P (2007) Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP. J Biol Chem 282, 20999-21004 https://doi.org/10.1074/jbc.M700915200
  7. Hansen C, Rouhi R, Forster G and Kahaly GJ (1999) Increased sulfatation of orbital glycosaminoglycans in Graves' ophthalmopathy. J Clin Endocrinol Metab 84, 1409-1413 https://doi.org/10.1210/jcem.84.4.5609
  8. Korducki JM, Loftus SJ and Bahn RS (1992) Stimulation of glycosaminoglycan production in cultured human retroocular fibroblasts. Invest Ophthalmol Vis Sci 33, 2037-2042
  9. Wong YK, Tang KT, Wu JC, Hwang JJ and Wang HS (2001) Stimulation of hyaluronan synthesis by interleukin-1beta involves activation of protein kinase C betaII in fibroblasts from patients with Graves' ophthalmopathy. J Cell Biochem 82, 58-67 https://doi.org/10.1002/jcb.1118
  10. Wang HS, Tung WH, Tang KT et al (2005) TGF-beta induced hyaluronan synthesis in orbital fibroblasts involves protein kinase C betaII activation in vitro. J Cell Biochem 95, 256-267 https://doi.org/10.1002/jcb.20405
  11. Svennerholm L (1964) The Gangliosides. J Lipid Res 5, 145-155 https://doi.org/10.1016/S0022-2275(20)40231-7
  12. Nakamura K, Inagaki F and Tamai Y (1988) A novel ganglioside in dogfish brain. Occurrence of a trisialoganglioside with a sialic acid linked to N-acetylgalactosamine. J Biol Chem 263, 9896-9900 https://doi.org/10.1016/S0021-9258(19)81601-0
  13. Yu RK, Tsai YT, Ariga T and Yanagisawa M (2011) Structures, biosynthesis, and functions of gangliosides--an overview. J Oleo Sci 60, 537-544 https://doi.org/10.5650/jos.60.537
  14. Huwiler A, Kolter T, Pfeilschifter J and Sandhoff K (2000) Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta 1485, 63-99 https://doi.org/10.1016/S1388-1981(00)00042-1
  15. Kook KH, Choi YH, Kim YR et al (2011) Altered ganglioside expression modulates the pathogenic mechanism of thyroid-associated ophthalmopathy by increase in hyaluronic acid. Invest Ophthalmol Vis Sci 52, 264-273 https://doi.org/10.1167/iovs.10-5276
  16. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655-1657 https://doi.org/10.1126/science.296.5573.1655
  17. Yoon HJ, Jeon SB, Suk K, Choi DK, Hong YJ and Park EJ (2008) Contribution of TLR2 to the initiation of ganglioside-triggered inflammatory signaling. Mol Cells 25, 99-104
  18. Liu YD, Ji CB, Li SB et al (2018) Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K/Akt and NF-kappaB signaling pathways. Int Immunopharmacol 59, 375-383 https://doi.org/10.1016/j.intimp.2018.04.033
  19. Lim ST, Esfahani K, Avdoshina V and Mocchetti I (2011) Exogenous gangliosides increase the release of brain-derived neurotrophic factor. Neuropharmacology 60, 1160-1167 https://doi.org/10.1016/j.neuropharm.2010.10.012
  20. Kanda N and Tamaki K (1999) Ganglioside GT1b suppresses immunoglobulin production by human peripheral blood mononuclear cells. Immunology 96, 628-633 https://doi.org/10.1046/j.1365-2567.1999.00734.x
  21. Kanda N and Watanabe S (2001) Gangliosides GD1b, GT1b, and GQ1b enhance IL-2 and IFN-gamma production and suppress IL-4 and IL-5 production in phytohemagglutininstimulated human T cells. J Immunol 166, 72-80 https://doi.org/10.4049/jimmunol.166.1.72
  22. Hsieh AC, Truitt ML and Ruggero D (2011) Oncogenic AKTivation of translation as a therapeutic target. Br J Cancer 105, 329-336 https://doi.org/10.1038/bjc.2011.241
  23. Juric D, Krop I, Ramanathan RK et al (2017) Phase I dose-escalation study of taselisib, an oral pi3k inhibitor, in patients with advanced solid tumors. Cancer Discov 7, 704-715 https://doi.org/10.1158/2159-8290.CD-16-1080
  24. Dreyling M, Santoro A, Mollica L et al (2017) Phosphatidylinositol 3-Kinase Inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 35, 3898-3905 https://doi.org/10.1200/JCO.2017.75.4648
  25. Raphael J, Desautels D, Pritchard KI, Petkova E and Shah PS (2018) Phosphoinositide 3-kinase inhibitors in advanced breast cancer: A systematic review and meta-analysis. Eur J Cancer 91, 38-46 https://doi.org/10.1016/j.ejca.2017.12.010
  26. Xu J and Liao K (2004) Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J Biol Chem 279, 35914-35922 https://doi.org/10.1074/jbc.M402297200
  27. Zhang L, Grennan-Jones F, Lane C, Rees DA, Dayan CM and Ludgate M (2012) Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves' orbitopathy. J Clin Endocrinol Metab 97, 653-662 https://doi.org/10.1210/jc.2011-1299
  28. Kumar S, Nadeem S, Stan MN, Coenen M and Bahn RS (2011) A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves' ophthalmopathy. J Mol Endocrinol 46, 155-163 https://doi.org/10.1530/JME-11-0006
  29. Li B and Smith TJ (2014) PI3K/AKT pathway mediates induction of IL-1RA by TSH in fibrocytes: modulation by PTEN. J Clin Endocrinol Metab 99, 3363-3372 https://doi.org/10.1210/jc.2014-1257
  30. Thaiss CA, Levy M, Itav S and Elinav E (2016) Integration of Innate Immune Signaling. Trends Immunol 37, 84-101 https://doi.org/10.1016/j.it.2015.12.003
  31. Kawasaki T and Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5, 461
  32. Lim HS, Back KO, Kim HJ, Choi YH, Park YM and Kook KH (2014) Hyaluronic acid induces COX-2 expression via CD44 in orbital fibroblasts from patients with thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 55, 7441-7450 https://doi.org/10.1167/iovs.14-14873
  33. Kaback LA and Smith TJ (1999) Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 84, 4079-4084 https://doi.org/10.1210/jcem.84.11.6111
  34. Zhang L, Bowen T, Grennan-Jones F et al (2009) Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: contributory role in hyaluronan accumulation in thyroid dysfunction. J Biol Chem 284, 26447-26455 https://doi.org/10.1074/jbc.M109.003616
  35. Pasonen-Seppanen S, Takabe P, Edward M et al (2012) Melanoma cell-derived factors stimulate hyaluronan synthesis in dermal fibroblasts by upregulating HAS2 through PDGFRPI3K-AKT and p38 signaling. Histochem Cell Biol 138, 895-911 https://doi.org/10.1007/s00418-012-1000-x
  36. Qin J, Berdyshev E, Poirer C, Schwartz NB and Dawson G (2012) Neutral sphingomyelinase 2 deficiency increases hyaluronan synthesis by up-regulation of hyaluronan synthase 2 through decreased ceramide production and activation of Akt. J Biol Chem 287, 13620-13632 https://doi.org/10.1074/jbc.M111.304857
  37. Kultti A, Karna R, Rilla K et al (2010) Methyl-beta-cyclodextrin suppresses hyaluronan synthesis by down-regulation of hyaluronan synthase 2 through inhibition of Akt. J Biol Chem 285, 22901-22910 https://doi.org/10.1074/jbc.M109.088435
  38. Manning BD and Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274 https://doi.org/10.1016/j.cell.2007.06.009