Journal of Neuroimmune Pharmacology

, Volume 8, Issue 3, pp 643–650 | Cite as

Glia Maturation Factor Induces Interleukin-33 Release from Astrocytes: Implications for Neurodegenerative Diseases

  • Duraisamy Kempuraj
  • Mohammad Moshahid Khan
  • Ramasamy Thangavel
  • Zhi Xiong
  • Evert Yang
  • Asgar Zaheer


Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Multiple sclerosis (MS) involve activation of glial cells and release of inflammatory mediators leading to death of neurons. Glia maturation factor (GMF) is up-regulated in the central nervous system (CNS) in these neurodegenerative diseases. Interleukin-33 (IL-33) is highly expressed constitutively in the CNS. We have treated mouse astrocytes, mixed culture with glial cells and neurons, and only neurons with GMF and/or IL-33 in vitro. Both GMF and IL-33-induced chemokine (C-C motif) ligand 2 (CCL2) release in a dose and time-dependent manner. We report that GMF induced IL-33 release, and that IL-33 augments GMF-induced tumor necrosis factor-alpha (TNF-α) release from mouse astrocytes. IL-33 induces CCL2, TNF-α and nitric oxide release through phosphorylation of ERK in mouse astrocytes. Incubation of mixed culture containing glial cells and neurons or only neuronal culture with IL-33 reduced the number of neurons positive for microtubule-associated protein 2. In conclusion, IL-33 augments GMF-mediated neuroinflammation and may provide a new drug target for neurodegenerative and autoimmune diseases.


CCL2 Glia maturation factor Interleukin-33 Microtubule-associated protein 2 Neurodegenerative diseases TNF-α 


  1. Andre R, Lerouet D, Kimber I, Pinteaux E, Rothwell NJ (2005) Regulation of expression of the novel IL-1 receptor family members in the mouse brain. J Neurochem 95:324–330PubMedCrossRefGoogle Scholar
  2. Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA (2007) IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol 179:2551–2555PubMedGoogle Scholar
  3. Chapuis J, Hot D, Hansmannel F, Kerdraon O, Ferreira S, Hubans C, Maurage CA, Huot L, Bensemain F, Laumet G, Ayral AM, Fievet N, Hauw JJ, DeKosky ST, Lemoine Y, Iwatsubo T, Wavrant-Devrieze F, Dartigues JF, Tzourio C, Buee L, Pasquier F, Berr C, Mann D, Lendon C, Alperovitch A, Kamboh MI, Amouyel P, Lambert JC (2009) Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease. Mol Psychiatry 14:1004–1016PubMedCrossRefGoogle Scholar
  4. Choi YS, Choi HJ, Min JK, Pyun BJ, Maeng YS, Park H, Kim J, Kim YM, Kwon YG (2009) Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 114:3117–3126PubMedCrossRefGoogle Scholar
  5. Christophi GP, Gruber RC, Panos M, Christophi RL, Jubelt B, Massa PT (2012) Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol 142:308–319PubMedCrossRefGoogle Scholar
  6. Conductier G, Blondeau N, Guyon A, Nahon JL, Rovere C (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 224:93–100PubMedCrossRefGoogle Scholar
  7. Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190PubMedCrossRefGoogle Scholar
  8. Espinassous Q, Garcia-de-Paco E, Garcia-Verdugo I, Synguelakis M, von Aulock S, Sallenave JM, McKenzie AN, Kanellopoulos J (2009) IL-33 enhances lipopolysaccharide-induced inflammatory cytokine production from mouse macrophages by regulating lipopolysaccharide receptor complex. J Immunol 183:1446–1455PubMedCrossRefGoogle Scholar
  9. Farfara D, Lifshitz V, Frenkel D (2008) Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer’s disease. J Cell Mol Med 12:762–780PubMedCrossRefGoogle Scholar
  10. Galimberti D, Fenoglio C, Lovati C, Venturelli E, Guidi I, Corra B, Scalabrini D, Clerici F, Mariani C, Bresolin N, Scarpini E (2006) Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer’s disease. Neurobiol Aging 27:1763–1768Google Scholar
  11. Han P, Mi WL, Wang YQ (2011) Research progress on interleukin-33 and its roles in the central nervous system. Neurosci Bull 27:351–357PubMedCrossRefGoogle Scholar
  12. Hsu CL, Neilsen CV, Bryce PJ (2010) IL-33 is produced by mast cells and regulates IgE-dependent inflammation. PLoS One 5:e11944Google Scholar
  13. Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT (2008) Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol 84:631–643PubMedCrossRefGoogle Scholar
  14. Jana M, Anderson JA, Saha RN, Liu X, Pahan K (2005) Regulation of inducible nitric oxide synthase in proinflammatory cytokine-stimulated human primary astrocytes. Free Radic Biol Med 38:655–664PubMedCrossRefGoogle Scholar
  15. Jiang HR, Milovanović M, Allan D, Niedbala W, Besnard AG, Fukada SY, Alves-Filho JC, Togbe D, Goodyear CS, Linington C, Xu D, Lukic ML, Liew FY (2012) IL-33 attenuates EAE by suppressing IL-17 and IFN-γ production and inducing alternatively activated macrophages. Eur J Immunol 42:1804–1814PubMedCrossRefGoogle Scholar
  16. Kaplan R, Zaheer A, Jaye M, Lim R (1991) Molecular cloning and expression of biologically active human glia maturation factor-beta. J Neurochem 57:483–490PubMedCrossRefGoogle Scholar
  17. Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, Ransohoff RM, Ikezu T (2009) CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction. PLoS One 4:e6197PubMedCrossRefGoogle Scholar
  18. Lee Y, Aono M, Laskowitz D, Warner DS, Pearlstein RD (2004) Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity. Neurochem Int 44:107–118PubMedCrossRefGoogle Scholar
  19. Li M, Li Y, Liu X, Gao X, Wang Y (2012) IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neuroimmunol 247:25–31PubMedCrossRefGoogle Scholar
  20. Lim R, Miller JF, Zaheer A (1989) Purification and characterization of glia maturation factor beta: a growth regulator for neurons and glia. Proc Natl Acad Sci USA 86:3901–3905PubMedCrossRefGoogle Scholar
  21. Marx CE, Jarskog LF, Lauder JM, Lieberman JA, Gilmore JH (2001) Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia. Biol Psychiatry 50:743–749PubMedCrossRefGoogle Scholar
  22. Miljkovic D, Timotijevic G, Mostarica Stojkovic M (2011) Astrocytes in the tempest of multiple sclerosis. FEBS Lett 585:3781–3788PubMedCrossRefGoogle Scholar
  23. Milovanovic M, Volarevic V, Ljujic B, Radosavljevic G, Jovanovic I, Arsenijevic N, Lukic ML (2012) Deletion of IL-33R (ST2) abrogates resistance to EAE in BALB/C mice by enhancing polarization of APC to inflammatory phenotype. PLoS One 7:e45225Google Scholar
  24. Monnet-Tschudi F, Defaux A, Braissant O, Cagnon L, Zurich MG (2011) Methods to assess neuroinflammation. Curr Protoc Toxicol Chapter 12:Unit12 19 doi: 10.1002/0471140856. tx1219s50
  25. Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, Van Rooijen N, Andjelkovic AV (2005) Monocyte chemoattractant protein-1 regulation of blood–brain barrier permeability. Blood Flow 25:593–606CrossRefGoogle Scholar
  26. Thangavel R, Stolmeier D, Yang X, Anantharam P, Zaheer A (2012) Expression of glia maturation factor in neuropathological lesions of alzheimer’s disease. Neuropathol Appl Neurobiol 38:572–581PubMedCrossRefGoogle Scholar
  27. Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, Alysandratos KD, Kalogeromitros D, Asadi S, Stavrianeas N, Peterson E, Leeman S, Conti P (2010) IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA 107:4448–4453PubMedCrossRefGoogle Scholar
  28. Venters HD, Dantzer R, Kelley KW (2000) A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci 23:175–180PubMedCrossRefGoogle Scholar
  29. Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O (2012) CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS One 7:e30525PubMedCrossRefGoogle Scholar
  30. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453–457PubMedCrossRefGoogle Scholar
  31. Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, Saito H, Matsuda A (2010) IL-33 mediates inflammatory responses in human lung tissue cells. J Immunol 185:5743–5750PubMedCrossRefGoogle Scholar
  32. Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A (2011) Production and functions of IL-33 in the central nervous system. Brain Res 1385:8–17PubMedCrossRefGoogle Scholar
  33. Zaheer A, Mathur SN, Lim R (2002) Overexpression of glia maturation factor in astrocytes leads to immune activation of microglia through secretion of granulocyte-macrophage-colony stimulating factor. Biochem Biophys Res Commun 294:238–244PubMedCrossRefGoogle Scholar
  34. Zaheer A, Yorek MA, Lim R (2001) Effects of glia maturation factor overexpression in primary astrocytes on MAP kinase activation, transcription factor activation, and neurotrophin secretion. Neurochem Res 26:1293–1299PubMedCrossRefGoogle Scholar
  35. Zaheer A, Zaheer S, Sahu SK, Knight S, Khosravi H, Mathur SN, Lim R (2007) A novel role of glia maturation factor: induction of granulocyte-macrophage colony-stimulating factor and pro-inflammatory cytokines. J Neurochem 101:364–376PubMedCrossRefGoogle Scholar
  36. Zaheer S, Thangavel R, Sahu SK, Zaheer A (2011) Augmented expression of glia maturation factor in Alzheimer’s disease. Neuroscience 194:227–233PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Duraisamy Kempuraj
    • 1
    • 2
  • Mohammad Moshahid Khan
    • 2
  • Ramasamy Thangavel
    • 1
    • 2
  • Zhi Xiong
    • 2
  • Evert Yang
    • 1
  • Asgar Zaheer
    • 1
    • 2
  1. 1.VA Health Care SystemIowa CityUSA
  2. 2.Department of Neurology, Carver College of MedicineUniversity of Iowa Hospitals and ClinicsIowa CityUSA

Personalised recommendations