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The effects of Foxp3 on gene expression profiles in activated microglial cells

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Abstract

Microglia constitutes the first line of defense against infection and injury in the brain. We previously demonstrated that activated microglia express the Foxp3 gene. However, the role of Foxp3 in cells other than Treg is generally unknown. Therefore, this study was conducted to determine the effects of Foxp3 in LPS-induced activation of microglial cells. The effects of Foxp3 on gene expression profiles in activated microglial cells were evaluated by microarray analysis, which revealed that the Warburg effect, cytokine-cytokine receptor interaction, immune and inflammatory response, Jak-STAT signaling pathway, MAPK signaling pathway, cell adhesion molecules, p53 signaling pathway, and Wnt signaling pathway-related genes were up-regulated in LPS-treated Foxp3-deficient microglial cells. These findings indicate that Foxp3 might regulate the Warburg effect and inflammatory response in activated microglial cells.

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References

  1. Jiang, Y. et al. TLR4 signaling induces functional nerve growth factor receptor p75 (NTR) on mouse dendritic cells via p38MAPK and NF-kappaB pathways. Mol Immunol 45:1557–1566 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Ock, J. et al. Regulation of Toll-like receptor 4 expression and its signaling by hypoxia in cultured microglia. J Neurosci Res 85:1989–1995 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Kim, W. K. et al. A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuropharmacology 47:243–252 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Nagai, A. et al. Immortalized human microglial cell line: phenotypic expression. J Neurosci Res 81:342–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Seo, W. G. et al. Inhibitory effect of ethyl acetate fraction from Cudrania tricuspidata on the expression of nitric oxide synthase gene in RAW 264.7 macrophages stimulated with interferon-gamma and lipopolysaccharide. Gen Pharmacol 35:21–28 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Sohn, S. H. et al. Inhibition effects of Vitex rotundifolia on inflammatory gene expression in A549 human epithelial cells. Ann Allergy Asthma Immunol 103:152–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD 25+ regulatory T cells. Nat Immunol 4:330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10:1000–1007 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Duarte, J. H., Zelenay, S., Bergman, M. L., Martins, A. C. & Demengeot, J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 39:948–955 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches. Science 323:1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Newington, J. T. et al. Amyloid Beta resistance in nerve cell lines is mediated by the warburg effect. PLoS One 6:e19191.

  14. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Saura, J., Tusell, J. M. & Serratosa, J. High-yield isolation of murine microglia by mild trypsinization. Glia 44:183–189 (2003).

    Article  PubMed  Google Scholar 

  16. Kim, C. S. et al. Effect of various implant coatings on biological responses in MG63 using cDNA microarray. J Oral Rehabil 33:368–379 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, Y. et al. Large scale real-time PCR validation on gene expression measurements from two commercial long-oligonucleotide microarrays. BMC Genomics 7:59 (2006).

    Article  PubMed  Google Scholar 

  18. Chung, H. S. et al. Foxp3 is a novel repressor of microglia activation. Glia 58:1247–1256.

  19. Carmeliet, P. et al. Role of HIF-1alpha in hypoxiamediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Freeman, R. S. & Barone, M. C. Targeting hypoxiainducible factor (HIF) as a therapeutic strategy for CNS disorders. Curr Drug Targets CNS Neurol Disord 4:85–92 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Katschinski, D. M. Is there a molecular connection between hypoxia and aging? Exp Gerontol 41:482–484 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9:609–617 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Zinkernagel, A. S., Johnson, R. S. & Nizet, V. Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med 85:1339–1346 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Fraisl, P., Aragones, J. & Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 8:139–152 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Semenza, G. L. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185 (2006).

    Article  PubMed  Google Scholar 

  28. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28:445–489 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Wei, L., Laurence, A., Elias, K. M. & O’shea, J. J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 282:34605–34610 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory T (H)17 cells. Nature 448:484–487 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Akundi, R. S. et al. Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia. Glia 51:199–208 (2005).

    Article  PubMed  Google Scholar 

  37. Raines, K. W. et al. Nitric oxide inhibition of ERK1/2 activity in cells expressing neuronal nitric-oxide synthase. J Biol Chem 279:3933–3940 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Zaragoza, C. et al. Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells. Mol Pharmacol 62:927–935 (2002).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Hyunsu Bae.

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Sohn, SH., Lee, JH., Chung, HS. et al. The effects of Foxp3 on gene expression profiles in activated microglial cells. Mol. Cell. Toxicol. 8, 139–148 (2012). https://doi.org/10.1007/s13273-012-0017-5

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  • DOI: https://doi.org/10.1007/s13273-012-0017-5

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