Skip to main content
Log in

Involvement of CtBP2 in LPS-induced microglial activation

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

CtBP2 (C-terminal binding protein 2), which is widely expressed during developmental processes and differentiation, acts as a transcriptional repressor following recruitment to target promoters through repressors or other co-repressor proteins. In this study, we elucidated the dynamic expression changes and localization of CtBP2 in lipopolysaccharide (LPS)-induced neuroinflammatory processes in adult rats. CtBP2 expression was strongly induced in active glia cells (microglia and astrocytes) in inflamed spinal cord. In vitro studies indicated that the up-regulation of CtBP2 may be involved in the subsequent microglia activation following LPS exposure. And the knock-down of CtBP2 in microglia cell line HAPI by siRNA showed that CtBP2 increased the activation of microglia induced by LPS. Collectively, these results suggested CtBP2 may be important in host defense in microglia-mediated immune response. Understanding the cell signal pathway may provide a novel strategy against inflammatory and immune reaction in neuroinflammation in central nervous system.

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

Access this article

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

Similar content being viewed by others

Abbreviations

CtBP2:

C-terminal binding protein 2

LPS:

Lipopolysaccharide

CNS:

Central nervous system

FCS:

Fetal calf serum

TNF-α:

Tumor necrosis factor-α

BCL-3:

B-cell lymphoma 3

PAGE:

Polyacrylamide gel electrophoresis

ECL:

Enhanced chemiluminescence system

RT-PCR:

Reverse transcriptase PCR

GFAP:

Glial fibrillary acidic protein

NeuN:

Neuronal nuclei

PCNA:

Proliferating cell nuclear antigen

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

References

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  PubMed  CAS  Google Scholar 

  • Amat JA, Ishiguro H, Nakamura K, Norton WT (1996) Phenotypic diversity and kinetics of proliferating microglia and astrocytes following cortical stab wounds. Glia 16:368–382

    Article  PubMed  CAS  Google Scholar 

  • Blander JM, Medzhitov R (2004) Regulation of phagosome maturation by signals from toll-like receptors. Science 304:1014–1018

    Article  PubMed  CAS  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  PubMed  CAS  Google Scholar 

  • Boyd JM, Subramanian T, Schaeper U, La Regina M, Bayley S, Chinnadurai G (1993) A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J 12:469–478

    PubMed  CAS  Google Scholar 

  • Brannon M, Brown JD, Bates R, Kimelman D, Moon RT (1999) XCtBP is a XTcf-3 corepressor with roles throughout Xenopus development. Development 126:3159–3170

    PubMed  CAS  Google Scholar 

  • Carmody RJ, Ruan Q, Palmer S, Hilliard B, Chen YH (2007) Negative regulation of toll-like receptor signaling by NF-kappaB p50 ubiquitination blockade. Science 317:675–678

    Article  PubMed  CAS  Google Scholar 

  • Chao CC, Hu S, Peterson PK (1995) Glia, cytokines, and neurotoxicity. Crit Rev Neurobiol 9:189–205

    PubMed  CAS  Google Scholar 

  • Cheepsunthorn P, Radov L, Menzies S, Reid J, Connor JR (2001) Characterization of a novel brain-derived microglial cell line isolated from neonatal rat brain. Glia 35:53–62

    Article  PubMed  CAS  Google Scholar 

  • Chinnadurai G (2002) CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol Cell 9:213–224

    Article  PubMed  CAS  Google Scholar 

  • Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A (1999) The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators. Oncogene 18:3316–3323

    Article  PubMed  CAS  Google Scholar 

  • Deconinck AE, Mead PE, Tevosian SG, Crispino JD, Katz SG, Zon LI, Orkin SH (2000) FOG acts as a repressor of red blood cell development in Xenopus. Development 127:2031–2040

    PubMed  CAS  Google Scholar 

  • Doyle SE, O’Connell RM, Miranda GA, Vaidya SA, Chow EK, Liu PT, Suzuki S, Suzuki N, Modlin RL, Yeh WC, Lane T, Cheng G (2004) Toll like receptors induce a phagocytic gene program through p38. J Exp Med 199:81–90

    Article  PubMed  CAS  Google Scholar 

  • Felts PA, Woolston AM, Fernando HB, Asquith S, Gregson NA, Mizzi OJ, Smith KJ (2005) Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide. Brain 128:1649–1666

    Article  PubMed  Google Scholar 

  • Fujita T, Nolan GP, Liou HC, Scott ML, Baltimore D (1993) The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-kappa B p50 homodimers. Genes Dev 7:1354–1363

    Article  PubMed  CAS  Google Scholar 

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  PubMed  CAS  Google Scholar 

  • Hildebrand JD, Soriano P (2002) Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development. Mol Cell Biol 22:5296–5307

    Article  PubMed  CAS  Google Scholar 

  • Kato H, Takahashi A, Itoyama Y (2003) Cell cycle protein expression in proliferating microglia and astrocytes following transient global cerebral ischemia in the rat. Brain Res Bull 60:215–221

    Article  PubMed  CAS  Google Scholar 

  • Keutgens A, Shostak K, Close P, Zhang X, Hennuy B, Aussems M, Chapelle JP, Viatour P, Gothot A, Fillet M, Chariot A (2010) The repressing function of the oncoprotein BCL-3 requires CtBP, while its polyubiquitination and degradation involve the E3 ligase TBLR1. Mol Cell Biol 30:4006–4021

    Article  PubMed  CAS  Google Scholar 

  • Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Article  PubMed  CAS  Google Scholar 

  • Kuwata H, Watanabe Y, Miyoshi H, Yamamoto M, Kaisho T, Takeda K, Akira S (2003) IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood 102:4123–4129

    Article  PubMed  CAS  Google Scholar 

  • Lee KS, Yang WI (1992) Comparison of brain tumor growth kinetics by proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) labeling. Yonsei Med J 33:265–271

    PubMed  CAS  Google Scholar 

  • Leung TH, Hoffmann A, Baltimore D (2004) One nucleotide in a kappaB site can determine cofactor specificity for NF-kappaB dimmers. Cell 118:453–464

    Article  PubMed  CAS  Google Scholar 

  • Li S, Chen PL, Subramanian T, Chinnadurai G, Tomlinson G, Osborne CK, Sharp ZD, Lee WH (1999) Binding of CtIP to the BRCA1 repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J Biol Chem 274:11334–11338

    Article  PubMed  CAS  Google Scholar 

  • Luo XG, Ding JQ, Chen SD (2010) Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodegener 5:12

    Article  PubMed  Google Scholar 

  • Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815

    Article  PubMed  Google Scholar 

  • Merrill JE (1992) Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological. Dev Neurosci 14:1–10

    Article  PubMed  CAS  Google Scholar 

  • Morris GF, Mathews MB (1989) Regulation of proliferating cell nuclear antigen during the cell cycle. J Biol Chem 264:13856–13864

    PubMed  CAS  Google Scholar 

  • Nguyen MD, Julien JP, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3:216–227

    Article  PubMed  CAS  Google Scholar 

  • Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple tlrs. J Immunol 173:3916–3924

    PubMed  CAS  Google Scholar 

  • Postigo AA, Dean DC (1999) ZEB represses transcription through interaction with the corepressor CtBP. Proc Natl Acad Sci USA 96:6683–6688

    Article  PubMed  CAS  Google Scholar 

  • Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71:635–700

    Article  PubMed  CAS  Google Scholar 

  • Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145

    Article  PubMed  CAS  Google Scholar 

  • Rivieccio MA, John GR, Song X, Suh HS, Zhao Y, Lee SC, Brosnan CF (2005) The cytokine IL-1β activates IFN response factor 3 in human fetal astrocytes in culture. J Immunol 174:3719–3726

    PubMed  CAS  Google Scholar 

  • Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59

    Article  PubMed  CAS  Google Scholar 

  • Saijo K, Collier JG, Li AC, Katzenellenbogen JA, Glass CK (2011) An ADIOL-ERbeta-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145:584–595

    Article  PubMed  CAS  Google Scholar 

  • Schaeper U, Boyd JM, Verma S, Uhlmann E, Subramanian T, Chinnadurai G (1995) Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc Natl Acad Sci USA 92:10467–10471

    Article  PubMed  CAS  Google Scholar 

  • Shih YT, Hsu YY, Chang FR, Wu YC, Lo YC (2010) 6-Hydroxycleroda-3,13-dien-15,16-olide protects neuronal cells from lipopolysaccharide-induced neurotoxicity through the inhibition of microglia-mediated inflammation. Planta Med 76:120–127

    Article  PubMed  CAS  Google Scholar 

  • Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    Article  PubMed  Google Scholar 

  • Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139

    Article  PubMed  Google Scholar 

  • Trinchieri G, Sher A (2007) Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179–190

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Lee S, Teh CE, Bunting K, Ma L, Shannon MF (2009) The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells. Int Immunol 21:227–235

    Article  PubMed  CAS  Google Scholar 

  • Wessells J, Baer M, Young HA, Claudio E, Brown K, Siebenlist U, Johnson PF (2004) BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. J Biol Chem 279:49995–50003

    Article  PubMed  CAS  Google Scholar 

  • Yu X, Baer R (2000) Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J Biol Chem 275:18541–18549

    Article  PubMed  CAS  Google Scholar 

  • Zhou HF, Liu XY, Niu DB, Li FQ, He QH, Wang XM (2005) Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol Dis 18:441–449

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30870320, No. 81070992 and No. 81172879); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Qiyun Wu or Chun Cheng.

Additional information

Guowei Zhang and Yaohua Yan contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, G., Yan, Y., Kang, L. et al. Involvement of CtBP2 in LPS-induced microglial activation. J Mol Hist 43, 327–334 (2012). https://doi.org/10.1007/s10735-012-9399-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-012-9399-x

Keywords

Navigation