Skip to main content

Advertisement

SpringerLink
Log in

IL-33 Is Induced by Amyloid-β Stimulation and Regulates Inflammatory Cytokine Production in Retinal Pigment Epithelium Cells

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Age-related macular degeneration (AMD) is the predominant cause of irreversible blindness in the elderly population. Despite intensive basic and clinical research, its pathogenesis remains unclear. However, evidence suggests that immunological and inflammatory factors contribute to the pathogenesis of AMD. A newly identified cytokine, IL-33, appears to be an important pro-inflammatory cytokine promoting tissue inflammation. In this study, IL-33 was increased through amyloid-beta1–40 (Aβ1–40) stimulation and regulated inflammatory cytokines including IL-6, IL-8, IL-1β, and TNF-α secretion using different signaling pathways in retinal pigment epithelium (RPE) cells. Furthermore, ST2L, the important component of the IL-33 receptor, was significantly increased following recombinant human IL-33 stimulation in RPE cells. These findings suggest that IL-33-mediated inflammatory responses in RPE cells are involved in the pathogenesis of AMD. Greater understanding of the inflammatory effect of IL-33 and its role in RPE cells should aid the development of future clinical therapeutics and enable novel pharmacological approaches towards the prevention of AMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Klein, R., T. Peto, A. Bird, and M.R. Vannewkirk. 2004. The epidemiology of age-related macular degeneration. American Journal of Ophthalmology 137: 486–495.

    Article  PubMed  Google Scholar 

  2. Kuehn, B.M. 2005. Gene discovery provides clues to cause of age-related macular degeneration. JAMA 293: 1841–1845.

    Article  PubMed  CAS  Google Scholar 

  3. Rodrigues, E.B. 2007. Inflammation in dry age-related macular degeneration. Ophthalmologica 221: 143–152.

    Article  PubMed  CAS  Google Scholar 

  4. Kijlstra, A., E. La Heij, and F. Hendrikse. 2005. Immunological factors in the pathogenesis and treatment of age-related macular degeneration. Ocular Immunology and Inflammation 13: 3–11.

    Article  PubMed  CAS  Google Scholar 

  5. Stolarski, B., M. Kurowska-Stolarska, P. Kewin, D. Xu, and F.Y. Liew. 2010. IL-33 exacerbates eosinophil-mediated airway inflammation. Journal of Immunology 185: 3472–3480.

    Article  CAS  Google Scholar 

  6. Mato, N., M. Bando, H. Yamasawa, T. Hosono, Y. Mizushina, M. Sata, G. Ohki, and Y. Sugiyama. 2010. Role of IL-33 in bronchial asthma. Nihon Kokyūki Gakkai Zasshi 48: 419–425.

    PubMed  Google Scholar 

  7. Prefontaine, D., J. Nadigel, F. Chouiali, S. Audusseau, A. Semlali, J. Chakir, J.G. Martin, and Q. Hamid. 2010. Increased IL-33 expression by epithelial cells in bronchial asthma. The Journal of Allergy and Clinical Immunology 125: 752–754.

    Article  PubMed  CAS  Google Scholar 

  8. Matsuyama, Y., H. Okazaki, H. Tamemoto, H. Kimura, Y. Kamata, K. Nagatani, T. Nagashima, M. Hayakawa, M. Iwamoto, T. Yoshio, et al. 2010. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. Journal of Rheumatology 37: 18–25.

    Article  PubMed  CAS  Google Scholar 

  9. Mok, M.Y., F.P. Huang, W.K. Ip, Y. Lo, F.Y. Wong, E.Y. Chan, K.F. Lam, and D. Xu. 2010. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford, England) 49: 520–527.

    Article  CAS  Google Scholar 

  10. Bressler, S.B., M.G. Maguire, N.M. Bressler, and S.L. Fine. 1990. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. Archives of Ophthalmology 108: 1442–1447.

    Article  PubMed  CAS  Google Scholar 

  11. Vinding, T. 1990. Occurrence of drusen, pigmentary changes and exudative changes in the macula with reference to age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmol (Copenh) 68: 410–414.

    Article  CAS  Google Scholar 

  12. Handa, J.T., N. Verzijl, H. Matsunaga, A. Aotaki-Keen, G.A. Lutty, J.M. te Koppele, T. Miyata, and L.M. Hjelmeland. 1999. Increase in the advanced glycation end product pentosidine in Bruch’s membrane with age. Investigative Ophthalmology and Visual Science 40: 775–779.

    PubMed  CAS  Google Scholar 

  13. Pauleikhoff, D., S. Zuels, G.S. Sheraidah, J. Marshall, A. Wessing, and A.C. Bird. 1992. Correlation between biochemical composition and fluorescein binding of deposits in Bruch’s membrane. Ophthalmology 99: 1548–1553.

    PubMed  CAS  Google Scholar 

  14. Anderson, D.H., K.C. Talaga, A.J. Rivest, E. Barron, G.S. Hageman, and L.V. Johnson. 2004. Characterization of beta amyloid assemblies in drusen: The deposits associated with aging and age-related macular degeneration. Experimental Eye Research 78: 243–256.

    Article  PubMed  CAS  Google Scholar 

  15. Dentchev, T., A.H. Milam, V.M. Lee, J.Q. Trojanowski, and J.L. Dunaief. 2003. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Molecular Vision 9: 184–190.

    PubMed  CAS  Google Scholar 

  16. Luibl, V., J.M. Isas, R. Kayed, C.G. Glabe, R. Langen, and J. Chen. 2006. Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. The Journal of Clinical Investigation 116: 378–385.

    Article  PubMed  CAS  Google Scholar 

  17. Mullins, R.F., S.R. Russell, D.H. Anderson, and G.S. Hageman. 2000. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. The FASEB Journal 14: 835–846.

    CAS  Google Scholar 

  18. Ning, A., J. Cui, E. To, K.H. Ashe, and J. Matsubara. 2008. Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Investigative Ophthalmology and Visual Science 49: 5136–5143.

    Article  PubMed  Google Scholar 

  19. Yoshida, T., K. Ohno-Matsui, S. Ichinose, T. Sato, N. Iwata, T.C. Saido, T. Hisatomi, M. Mochizuki, and I. Morita. 2005. The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. The Journal of Clinical Investigation 115: 2793–2800.

    Article  PubMed  CAS  Google Scholar 

  20. Kurji, K.H., J.Z. Cui, T. Lin, D. Harriman, S.S. Prasad, L. Kojic, and J.A. Matsubara. 2010. Microarray analysis identifies changes in inflammatory gene expression in response to amyloid-beta stimulation of cultured human retinal pigment epithelial cells. Investigative Ophthalmology and Visual Science 51: 1151–1163.

    Article  PubMed  Google Scholar 

  21. Chackerian, A.A., E.R. Oldham, E.E. Murphy, J. Schmitz, S. Pflanz, and R.A. Kastelein. 2007. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. Journal of Immunology 179: 2551–2555.

    CAS  Google Scholar 

  22. Oboki, K., T. Ohno, N. Kajiwara, H. Saito, and S. Nakae. 2010. IL-33 and IL-33 receptors in host defense and diseases. Allergology International 59: 143–160.

    Article  PubMed  CAS  Google Scholar 

  23. Schmitz, J., A. Owyang, E. Oldham, Y. Song, E. Murphy, T.K. McClanahan, G. Zurawski, M. Moshrefi, J. Qin, X. Li, et al. 2005. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23: 479–490.

    Article  PubMed  CAS  Google Scholar 

  24. Anderson, D.H., R.F. Mullins, G.S. Hageman, and L.V. Johnson. 2002. A role for local inflammation in the formation of drusen in the aging eye. American Journal of Ophthalmology 134: 411–431.

    Article  PubMed  CAS  Google Scholar 

  25. Donoso, L.A., D. Kim, A. Frost, A. Callahan, and G. Hageman. 2006. The role of inflammation in the pathogenesis of age-related macular degeneration. Survey of Ophthalmology 51: 137–152.

    Article  PubMed  Google Scholar 

  26. Meda, L., P. Baron, E. Prat, E. Scarpini, G. Scarlato, M.A. Cassatella, and F. Rossi. 1999. Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with beta-amyloid[25–35]. Journal of Neuroimmunology 93: 45–52.

    Article  PubMed  CAS  Google Scholar 

  27. Eikelenboom, P., E. van Exel, J.J. Hoozemans, R. Veerhuis, A.J. Rozemuller, and W.A. van Gool. 2010. Neuroinflammation—An early event in both the history and pathogenesis of Alzheimer’s disease. Neurodegenerative Diseases 7: 38–41.

    Article  PubMed  CAS  Google Scholar 

  28. He, F.Q., B.Y. Qiu, T.K. Li, Q. Xie, D.J. Cui, X.L. Huang, and H.T. Gan. 2011. Tetrandrine suppresses amyloid-beta-induced inflammatory cytokines by inhibiting NF-kappaB pathway in murine BV2 microglial cells. Int Immunopharmacol 11: 1220–1225.

    Article  PubMed  CAS  Google Scholar 

  29. Lindberg, C., M.L. Selenica, A. Westlind-Danielsson, and M. Schultzberg. 2005. Beta-amyloid protein structure determines the nature of cytokine release from rat microglia. Journal of Molecular Neuroscience 27: 1–12.

    Article  PubMed  CAS  Google Scholar 

  30. Liu, B., and J.S. Hong. 2003. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention. Journal of Pharmacology and Experimental Therapeutics 304: 1–7.

    Article  PubMed  CAS  Google Scholar 

  31. Veerhuis, R., R.S. Boshuizen, M. Morbin, G. Mazzoleni, J.J. Hoozemans, J.P. Langedijk, F. Tagliavini, J.P. Langeveld, and P. Eikelenboom. 2005. Activation of human microglia by fibrillar prion protein-related peptides is enhanced by amyloid-associated factors SAP and C1q. Neurobiology of Disease 19: 273–282.

    Article  PubMed  CAS  Google Scholar 

  32. Beltran, C.J., L.E. Nunez, D. Diaz-Jimenez, N. Farfan, E. Candia, C. Heine, F. Lopez, M.J. Gonzalez, R. Quera, and M.A. Hermoso. 2010. Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease. Inflammatory Bowel Diseases 16: 1097–1107.

    PubMed  Google Scholar 

  33. Seidelin, J.B., J.T. Bjerrum, M. Coskun, B. Widjaya, B. Vainer, and O.H. Nielsen. 2010. IL-33 is upregulated in colonocytes of ulcerative colitis. Immunology Letters 128: 80–85.

    Article  PubMed  CAS  Google Scholar 

  34. Manetti, M., L. Ibba-Manneschi, V. Liakouli, S. Guiducci, A.F. Milia, G. Benelli, A. Marrelli, M.L. Conforti, E. Romano, R. Giacomelli, et al. 2010. The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. Annals of the Rheumatic Diseases 69: 598–605.

    Article  PubMed  CAS  Google Scholar 

  35. Marvie, P., M. Lisbonne, A. L’Helgoualc’h, M. Rauch, B. Turlin, L. Preisser, K. Bourd-Boittin, N. Theret, H. Gascan, C. Piquet-Pellorce, et al. 2010. Interleukin-33 overexpression is associated with liver fibrosis in mice and humans. Journal of Cellular and Molecular Medicine 14: 1726–1739.

    Article  PubMed  CAS  Google Scholar 

  36. Moulin, D., O. Donze, D. Talabot-Ayer, F. Mezin, G. Palmer, and C. Gabay. 2007. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine 40: 216–225.

    Article  PubMed  CAS  Google Scholar 

  37. Iikura, M., H. Suto, N. Kajiwara, K. Oboki, T. Ohno, Y. Okayama, H. Saito, S.J. Galli, and S. Nakae. 2007. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Laboratory Investigation 87: 971–978.

    Article  PubMed  CAS  Google Scholar 

  38. Funakoshi-Tago, M., K. Tago, Y. Sato, S. Tominaga, and T. Kasahara. 2011. JAK2 is an important signal transducer in IL-33-induced NF-kappaB activation. Cellular Signalling 23: 363–370.

    Article  PubMed  CAS  Google Scholar 

  39. Yagami, A., K. Orihara, H. Morita, K. Futamura, N. Hashimoto, K. Matsumoto, H. Saito, and A. Matsuda. 2010. IL-33 mediates inflammatory responses in human lung tissue cells. Journal of Immunology 185: 5743–5750.

    Article  CAS  Google Scholar 

  40. Kunes, P., Z. Holubcova, M. Kolackova, and J. Krejsek. 2010. The counter-regulation of atherogenesis: A role for interleukin-33. Acta Medica (Hradec Králové) 53: 125–129.

    CAS  Google Scholar 

  41. Dinarello, C.A. 2009. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology 27: 519–550.

    Article  PubMed  CAS  Google Scholar 

  42. O’Neill, L.A. 2008. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunological Reviews 226: 10–18.

    Article  PubMed  Google Scholar 

  43. Suzukawa, M., M. Iikura, R. Koketsu, H. Nagase, C. Tamura, A. Komiya, S. Nakae, K. Matsushima, K. Ohta, K. Yamamoto, et al. 2008. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. Journal of Immunology 181: 5981–5989.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Chinese PLA (People’s Liberation Army) General Hospital, 28 Fuxing Road, Beijing, 100853, China

    Xiao-Cui Liu & Shou-Zhi He

  2. Department of Laboratory Medicine, General Hospital of Jinan Military Region of PLA, Jinan, Shandong Province, 250031, China

    Xiao-Fei Liu

  3. Department of Stomatolog, PLA General Hospital of Chengdu Military Region, Chengdu, Sichuan Province, 610083, China

    Cong-Xiang Jian & Chen-Jun Li

Authors
  1. Xiao-Cui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Fei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cong-Xiang Jian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen-Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shou-Zhi He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chen-Jun Li or Shou-Zhi He.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, XC., Liu, XF., Jian, CX. et al. IL-33 Is Induced by Amyloid-β Stimulation and Regulates Inflammatory Cytokine Production in Retinal Pigment Epithelium Cells. Inflammation 35, 776–784 (2012). https://doi.org/10.1007/s10753-011-9379-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-011-9379-4

KEY WORDS

Search

Navigation