본문 바로가기
KERD
논문KCI 등재

Ganglioside GT1b increases hyaluronic acid synthase 2 via PI3K activation with TLR2 dependence in orbital fibroblasts from thyroid eye disease patients

0

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류화학

초록

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 PI3Krelated signaling pathway, dependent on TLR2.

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 PI3Krelated signaling pathway, dependent on TLR2.

참고문헌 (38)

  1. Kazim M, "Insights into the pathogenesis of thyroid-associated orbitopathy : evolving rationale for therapy", Arch Ophthalmol, 120, pp.380~386 (2002)
  2. Garrity JA, "Pathogenesis of graves ophthalmopathy : implications for prediction, prevention, and treatment", Am J Ophthalmol, 142, pp.147~153 (2006)
  3. Naik VM, "Immunopathogenesis of thyroid eye disease : emerging paradigms", Surv Ophthalmol, 55, pp.215~226 (2010)
  4. Bahn RS, "Graves’ ophthalmopathy", N Engl J Med, 362, pp.726~738 (2010)
  5. Smith TJ, "Connective tissue, glycosaminoglycans, and diseases of the thyroid", Endocr Rev, 10, pp.366~391 (1989)
  6. Schulz T, "Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP", J Biol Chem, 282, pp.20999~21004 (2007)
  7. Hansen C, "Increased sulfatation of orbital glycosaminoglycans in Graves’ ophthalmopathy", J Clin Endocrinol Metab, 84, pp.1409~1413 (1999)
  8. Korducki JM, "Stimulation of glycosaminoglycan production in cultured human retroocular fibroblasts", Invest Ophthalmol Vis Sci, 33, pp.2037~2042 (1992)
  9. Wong YK, "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, pp.58~67 (2001)
  10. Wang HS, "TGF-beta induced hyaluronan synthesis in orbital fibroblasts involves protein kinase C betaII activation in vitro", J Cell Biochem, 95, pp.256~267 (2005)
  11. Svennerholm L, "The Gangliosides", J Lipid Res, 5, pp.145~155 (1964)
  12. Nakamura K, "A novel ganglioside in dogfish brain. Occurrence of a trisialoganglioside with a sialic acid linked to N-acetylgalactosamine", J Biol Chem, 263, pp.9896~9900 (1988)
  13. Yu RK, "Structures, biosynthesis, and functions of gangliosides--an overview", J Oleo Sci, 60, pp.537~544 (2011)
  14. Huwiler A, "Physiology and pathophysiology of sphingolipid metabolism and signaling", Biochim Biophys Acta, 1485, pp.63~99 (2000)
  15. Kook KH, "Altered ganglioside expression modulates the pathogenic mechanism of thyroid-associated ophthalmopathy by increase in hyaluronic acid", Invest Ophthalmol Vis Sci, 52, pp.264~273 (2011)
  16. Cantley LC, "The phosphoinositide 3-kinase pathway", Science, 296, pp.1655~1657 (2002)
  17. 윤희정, "Contribution of TLR2 to the Initiation of Ganglioside-triggered Inflammatory Signaling", Molecules and Cells, 25(1), pp.99~104 (2008), 한국분자세포생물학회
  18. Liu YD, "Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K", Akt and NF-kappaB signaling pathways, 2018, pp.59, 375~383
  19. Lim ST, "Exogenous gangliosides increase the release of brain-derived neurotrophic factor", Neuropharmacology, 60, pp.1160~1167 (2011)
  20. Kanda N, "Ganglioside GT1b suppresses immunoglobulin production by human peripheral blood mononuclear cells", Immunology, 96, pp.628~633 (1999)
  21. Kanda N, "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, pp.72~80 (2001)
  22. Hsieh AC, "Oncogenic AKTivation of translation as a therapeutic target", Br J Cancer, 105, pp.329~336 (2011)
  23. Juric D, "Phase I dose-escalation study of taselisib, an oral pi3k inhibitor, in patients with advanced solid tumors", Cancer Discov, 7, pp.704~715 (2017)
  24. Dreyling M, "Phosphatidylinositol 3-Kinase Inhibition by copanlisib in relapsed or refractory indolent lymphoma", J Clin Oncol, 35, pp.3898~3905 (2017)
  25. Raphael J, "Phosphoinositide 3-kinase inhibitors in advanced breast cancer : A systematic review and meta-analysis", Eur J Cancer, 91, pp.38~46 (2018)
  26. Xu J, "Protein kinase B", AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation, 2004, pp.279, 35914~35922
  27. Zhang L, "Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves’ orbitopathy", J Clin Endocrinol Metab, 97, pp.653~662 (2012)
  28. Kumar S, "A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves’ ophthalmopathy", J Mol Endocrinol, 46, pp.155~163 (2011)
  29. Li B, "PI3K", AKT pathway mediates induction of IL-1RA by TSH in fibrocytes : modulation by PTEN, 2014, pp.99, 3363~3372
  30. Thaiss CA, "Integration of Innate Immune Signaling", Trends Immunol, 37, pp.84~101 (2016)
  31. Kawasaki T, "Toll-like receptor signaling pathways", Front Immunol, 5, pp.461~ (2014)
  32. Lim HS, "Hyaluronic acid induces COX-2 expression via CD44 in orbital fibroblasts from patients with thyroid-associated ophthalmopathy", Invest Ophthalmol Vis Sci, 55, pp.7441~7450 (2014)
  33. Kaback LA, "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, pp.4079~4084 (1999)
  34. Zhang L, "Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts : contributory role in hyaluronan accumulation in thyroid dysfunction", J Biol Chem, 284, pp.26447~26455 (2009)
  35. Pasonen-Seppanen S, "Melanoma cell-derived factors stimulate hyaluronan synthesis in dermal fibroblasts by upregulating HAS2 through PDGFRPI3K-AKT and p38 signaling", Histochem Cell Biol, 138, pp.895~911 (2012)
  36. Qin J, "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, pp.13620~13632 (2012)
  37. Kultti A, "Methyl-beta-cyclodextrin suppresses hyaluronan synthesis by down-regulation of hyaluronan synthase 2 through inhibition of Akt", J Biol Chem, 285, pp.22901~22910 (2010)
  38. Manning BD, "AKT", PKB signaling : navigating downstream, 2007, pp.129, 1261~1274

관련 논문AI추천

이 간행물의 다른 논문 (8건)