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Glia Maturation Factor Regulation of STAT Expression: A Novel Mechanism in Experimental Autoimmune Encephalomyelitis

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Abstract

Inflammatory cytokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We previously demonstrated that glia maturation factor (GMF), a brain protein, isolated, sequenced and cloned in our laboratory, induce expression of proinflammatory cytokine/chemokine in the central nervous system (CNS). We found GMF-deficient (knockout) mice relatively resistant to EAE development after immunization with encephalitogenic MOG peptide 35–55. Consistent with these findings, the expression of proinflammatory cytokines in CNS of mice with EAE differed profoundly between wild type and GMF-knockout mice. In the present study we examined the expressions of six murine signal transducers and activators of transcription (STATs) genes, which are known to regulate the cytokine-dependent signal transduction pathways in autoimmune inflammation. The expressions of STATs genes were evaluated in the brains and spinal cords of wild type and GMF-knockout mice at the peak of EAE by quantitative real-time RT-PCR. Compared to GMF-knockout mice, the expressions of STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6 genes were significantly (P < 0.001) upregulated in the wild type mice exhibiting EAE symptoms. The results are consistent with the diminished development of EAE in the GMF-knockout mice. A significant suppression of STATs expression in GMF-knockout mice suggests GMF as an upstream effector of JAK/STAT signaling.

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Abbreviations

GMF:

Glia maturation factor

RT-PCR:

Reverse transcription-polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

STAT:

Signal transducers and activators of transcription

MOG:

Myelin oligodendrocyte glycoprotein

MS:

Multiple sclerosis

EAE:

Experimental autoimmune encephalomyelitis

References

  1. Kaplan R, Zaheer A, Jaye M, Lim R (1991) Molecular cloning and expression of biologically active human glia maturation factor-beta. J Neurochem 57:483–490

    Article  PubMed  CAS  Google Scholar 

  2. 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 U S A 86:3901–3905

    Article  PubMed  CAS  Google Scholar 

  3. Lim R, Zaheer A, Lane WS (1990) Complete amino acid sequence of bovine glia maturation factor beta. Proc Natl Acad Sci USA 87:5233–5237

    Article  PubMed  CAS  Google Scholar 

  4. Wang BR, Zaheer A, Lim R (1992) Polyclonal antibody localizes glia maturation factor beta-like immunoreactivity in neurons and glia. Brain Res 591:1–7

    Article  PubMed  CAS  Google Scholar 

  5. Lander ES (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    Article  PubMed  CAS  Google Scholar 

  6. Zaheer A, Fink BD, Lim R (1993) Expression of glia maturation factor beta mRNA and protein in rat organs and cells. J Neurochem 60:914–920

    Article  PubMed  CAS  Google Scholar 

  7. 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 101:364–376

    Article  PubMed  CAS  Google Scholar 

  8. Zaheer A, Sahu SK, Wu Y, Zaheer A, Haas J, Lee K, Yang B (2007) Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis. Brain Res 1144:239–247

    Article  PubMed  CAS  Google Scholar 

  9. Zaheer A, Zaheer S, Sahu SK, Yang B, Lim R (2007) Reduced severity of experimental autoimmune encephalomyelitis in GMF-deficient mice. Neurochem Res 32:39–47

    Article  PubMed  CAS  Google Scholar 

  10. Jee Y, Kim G, Tanuma N, Matsumoto Y (2001) STAT expression and localization in the central nervous system during autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol 114:40–47

    Article  PubMed  CAS  Google Scholar 

  11. Maier J, Kincaid C, Pagenstecher A, Campbell IL (2002) Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis. Am J Pathol 160:271–288

    PubMed  CAS  Google Scholar 

  12. Ransohoff RM (1998) Cellular responses to interferons and other cytokines: the JAK-STAT paradigm. N Engl J Med 338:616–618

    Article  PubMed  CAS  Google Scholar 

  13. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–633

    Article  PubMed  CAS  Google Scholar 

  14. Lim R, Zaheer A, Khosravi H, Freeman JH Jr, Halverson HE, Wemmie JA, Yang B (2004) Impaired motor performance and learning in glia maturation factor-knockout mice. Brain Res 1024:225–232

    Article  PubMed  CAS  Google Scholar 

  15. Zaheer A, Haas JT, Reyes C, Mathur SN, Yang B, Lim R (2006) GMF-knockout mice are unable to induce brain-derived neurotrophic factor after exercise. Neurochem Res 31:579–584

    Article  PubMed  CAS  Google Scholar 

  16. Zaheer A, Yang B, Cao X, Lim R (2004) Decreased copper-zinc superoxide dismutase activity and increased resistance to oxidative stress in glia maturation factor-null astrocytes. Neurochem Res 29:1473–1480

    Article  PubMed  CAS  Google Scholar 

  17. Lim R, Zaheer A (1996) In vitro enhancement of p38 mitogen-activated protein kinase activity by phosphorylated glia maturation factor. J Biol Chem 271:22953–22956

    Article  PubMed  CAS  Google Scholar 

  18. Zaheer A, Lim R (1996) In vitro inhibition of MAP kinase (ERK1/ERK2) activity by phosphorylated glia maturation factor (GMF). Biochemistry 35:6283–6288

    Article  PubMed  CAS  Google Scholar 

  19. Zaheer A, Lim R (1998) Overexpression of glia maturation factor (GMF) in PC12 pheochromocytoma cells activates p38 MAP kinase, MAPKAP kinase-2, and tyrosine hydroxylase. Biochem Biophys Res Commun 250:278–282

    Article  PubMed  CAS  Google Scholar 

  20. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  21. Zaheer A, Zhong W, Lim R (1995) Expression of mRNAs of multiple growth factors and receptors by neuronal cell lines: detection with RT-PCR. Neurochem Res 20:1457–1463

    Article  PubMed  CAS  Google Scholar 

  22. Zaheer A, Zhong W, Uc EY, Moser DR, Lim R (1995) Expression of mRNAs of multiple growth factors and receptors by astrocytes and glioma cells: detection with reverse transcription-polymerase chain reaction. Cell Mol Neurobiol 15:221–237

    Article  PubMed  CAS  Google Scholar 

  23. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  24. Genain CP, Hauser SL (2001) Experimental allergic encephalomyelitis in the New World monkey Callithrix jacchus. Immunol Rev 183:159–172

    Article  PubMed  CAS  Google Scholar 

  25. Iglesias A, Bauer J, Litzenburger T, Schubart A, Linington C (2001) T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 36:220–234

    Article  PubMed  CAS  Google Scholar 

  26. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952

    Article  PubMed  CAS  Google Scholar 

  27. Linington C, Berger T, Perry L, Weerth S, Hinze-Selch D, Zhang Y, Lu HC, Lassmann H, Wekerle H (1993) T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur J Immunol 23:1364–1372

    Article  PubMed  CAS  Google Scholar 

  28. Tuohy VK (1994) Peptide determinants of myelin proteolipid protein (PLP) in autoimmune demyelinating disease: a review. Neurochem Res 19:935–944

    Article  PubMed  CAS  Google Scholar 

  29. 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 294:238–244

    Article  PubMed  CAS  Google Scholar 

  30. Godiska R, Chantry D, Dietsch GN, Gray PW (1995) Chemokine expression in murine experimental allergic encephalomyelitis. J Neuroimmunol 58:167–176

    Article  PubMed  CAS  Google Scholar 

  31. Ransohoff RM, Glabinski A, Tani M (1996) Chemokines in immune-mediated inflammation of the central nervous system. Cytokine Growth Factor Rev 7:35–46

    Article  PubMed  CAS  Google Scholar 

  32. Hamilton NH, Banyer JL, Hapel AJ, Mahalingam S, Ramsay AJ, Ramshaw IA, Thomson SA (2002) IFN-gamma regulates murine interferon-inducible T cell alpha chemokine (I-TAC) expression in dendritic cell lines and during experimental autoimmune encephalomyelitis (EAE). Scand J Immunol 55:171–177

    PubMed  CAS  Google Scholar 

  33. Liu J, Marino MW, Wong G, Grail D, Dunn A, Bettadapura J, Slavin AJ, Old L, Bernard CC (1998) TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med 4:78–83

    Article  PubMed  CAS  Google Scholar 

  34. Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 161:6480–6486

    PubMed  CAS  Google Scholar 

  35. Becher B, Durell BG, Noelle RJ (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110:493–497

    Article  PubMed  CAS  Google Scholar 

  36. Natarajan C, Bright JJ (2002) Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun 3:59–70

    Article  PubMed  CAS  Google Scholar 

  37. Bhat NR, Feinstein DL, Shen Q, Bhat AN (2002) p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating transcription factor-2. J Biol Chem 277:29584–29592

    Article  PubMed  CAS  Google Scholar 

  38. Meja KK, Seldon PM, Nasuhara Y, Ito K, Barnes PJ, Lindsay MA, Giembycz MA (2000) p38 MAP kinase and MKK-1 co-operate in the generation of GM-CSF from LPS-stimulated human monocytes by an NF-kappa B-independent mechanism. Br J Pharmacol 131:1143–1153

    Article  PubMed  CAS  Google Scholar 

  39. Calza L, Giardino L, Pozza M, Micera A, Aloe L (1997) Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc Natl Acad Sci USA 94:3368–3373

    Article  PubMed  CAS  Google Scholar 

  40. Cross AH, Misko TP, Lin RF, Hickey WF, Trotter JL, Tilton RG (1994) Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J Clin Invest 93:2684–2690

    Article  PubMed  CAS  Google Scholar 

  41. Gollob JA, Schnipper CP, Murphy EA, Ritz J, Frank DA (1999) The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation. J Immunol 162:4472–4481

    PubMed  CAS  Google Scholar 

  42. Kim DH, Feinbaum R, Alloing G, Emerson FE, Garsin DA, Inoue H, Tanaka-Hino M, Hisamoto N, Matsumoto K, Tan MW, Ausubel FM (2002) A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297:623–626

    Article  PubMed  CAS  Google Scholar 

  43. Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, Frank DA, Holzman LB, Wu J, Sebti S, Jove R (1999) Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol 19:7519–7528

    PubMed  CAS  Google Scholar 

  44. Uddin S, Lekmine F, Sharma N, Majchrzak B, Mayer I, Young PR, Bokoch GM, Fish EN, Platanias LC (2000) The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. J Biol Chem 275:27634–27640

    PubMed  CAS  Google Scholar 

  45. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84

    Article  PubMed  CAS  Google Scholar 

  46. Natarajan C, Bright JJ (2002) Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes. J Immunol 168:6506–6513

    PubMed  CAS  Google Scholar 

  47. Kaplan MH, Sun YL, Hoey T, Grusby MJ (1996) Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382:174–177

    Article  PubMed  CAS  Google Scholar 

  48. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174

    Article  PubMed  CAS  Google Scholar 

  49. Dell’Albani P, Santangelo R, Torrisi L, Nicoletti VG, de Vellis J, Giuffrida Stella AM (2001) JAK/STAT signaling pathway mediates cytokine-induced iNOS expression in primary astroglial cell cultures. J Neurosci Res 65:417–424

    Article  PubMed  CAS  Google Scholar 

  50. Miscia S, Marchisio M, Grilli A, Di Valerio V, Centurione L, Sabatino G, Garaci F, Zauli G, Bonvini E, Di Baldassarre A (2002) Tumor necrosis factor alpha (TNF-alpha) activates Jak1/Stat3-Stat5B signaling through TNFR-1 in human B cells. Cell Growth Differ 13:13–18

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Shailendra Sahu, Marcus Ahrens, Ashna Zaheer, Scott Knight, Satya Mathur and Krishnakumar Menon for excellent technical help. This work was supported by the Department of Veterans Affairs Merit Review award (to A.Z.) and by the National Institute of Neurological Disorders and Stroke grant NS-47145 (to A.Z.).

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Authors and Affiliations

  1. Veterans Affair Medical Center, Iowa City, IA, USA

    Jon Bassett & Asgar Zaheer

  2. Division of Neurochemistry and Neurobiology, Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Yanghong Wu, Jon Bassett & Asgar Zaheer

  3. Department of Obstetric and Gynecology, University of Iowa, Iowa City, IA, 52242, USA

    Smita Zaheer & Baoli Yang

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  1. Smita Zaheer
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  2. Yanghong Wu
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  3. Jon Bassett
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  5. Asgar Zaheer
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Correspondence to Asgar Zaheer.

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Special issue in honor of Naren Banik.

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Zaheer, S., Wu, Y., Bassett, J. et al. Glia Maturation Factor Regulation of STAT Expression: A Novel Mechanism in Experimental Autoimmune Encephalomyelitis. Neurochem Res 32, 2123–2131 (2007). https://doi.org/10.1007/s11064-007-9383-0

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