Skip to main content
SpringerLink
Log in

Activation of STAT1 in Neurons Following Spinal Cord Injury in Mice

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The signal transducer and activator of transcription 1 (STAT1) has been reported to be associated with neuronal cell death after cerebral ischemia. On the contrary, STAT3 has been revealed to regulate cell survival. We examined the chronological alteration and cellular localization of phosphorylated (p)-JAK1, p-STAT1 and p-STAT3 following mild spinal cord injury (SCI) in mice. Western blot analysis indicated that JAK1 is significantly phosphorylated, accompanied by the phosphorylation of STAT1 at Tyr701 within a similar timeframe. Immunofluorescence staining indicated that signal transduction of STAT3 is introduced into the nucleus of the neurons within the anterior horns; however, in mirror sections, that of STAT1 is limited to the cytoplasm. These findings suggest that STAT3 signal is predominantly transduced into the nucleus and plays a stronger role in neuronal survival than STAT1. Modulation of the functional balance between STAT1 and STAT3 might determine the survival or death of neurons after SCI.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hayashi M, Ueyama T, Nemoto K et al (2000) Sequential mRNA expression for immediate early genes, cytokines, and neurotrophins in spinal cord injury. J Neurotrauma 17:203–218

    Article  PubMed  CAS  Google Scholar 

  2. Hirano T, Nakajima K, Hibi M (1997) Signaling mechanisms through gp130: a model of the cytokine system. Cytokine Growth Factor Rev 8:241–252

    Article  PubMed  CAS  Google Scholar 

  3. Cattaneo E, Conti L, De-Fraja C (1999) Signalling through the JAK-STAT pathway in the developing brain. Trends Neurosci 22:365–369

    Article  PubMed  CAS  Google Scholar 

  4. Schwaiger FW, Hager G, Schmitt AB et al (2000) Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT). Eur J Neurosci 12:1165–1176

    Article  PubMed  CAS  Google Scholar 

  5. Yao GL, Kato H, Khalil M et al (1997) Selective upregulation of cytokine receptor subchain and their intracellular signalling molecules after peripheral nerve injury. Eur J Neurosci 9:1047–1054

    Article  PubMed  CAS  Google Scholar 

  6. Dominguez E, Rivat C, Pommier B et al (2008) JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat. J Neurochem 107:50–60

    Article  PubMed  CAS  Google Scholar 

  7. Dominguez E, Mauborgne A, Mallet J et al (2010) SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury. J Neurosci 30:5754–5766

    Article  PubMed  CAS  Google Scholar 

  8. Herrmann JE, Imura T, Song B et al (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243

    Article  PubMed  CAS  Google Scholar 

  9. Okada S, Nakamura M, Katoh H et al (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829–834

    Article  PubMed  CAS  Google Scholar 

  10. Yamauchi K, Osuka K, Takayasu M et al (2006) Activation of JAK/STAT signalling in neurons following spinal cord injury in mice. J Neurochem 96:1060–1070

    Article  PubMed  CAS  Google Scholar 

  11. Xu J, Chen S, Chen H et al (2009) STAT5 mediates antiapoptotic effects of methylprednisolone on oligodendrocytes. J Neurosci 29:2022–2026

    Article  PubMed  CAS  Google Scholar 

  12. Takagi Y, Harada J, Chiarugi A et al (2002) STAT1 is activated in neurons after ischemia and contributes to ischemic brain injury. J Cereb Blood Flow Metab 22:1311–1318

    Article  PubMed  CAS  Google Scholar 

  13. West DA, Valentim LM, Lythgoe MF et al (2004) MR image-guided investigation of regional signal transducers and activators of transcription-1 activation in a rat model of focal cerebral ischemia. Neuroscience 127:333–339

    Article  PubMed  CAS  Google Scholar 

  14. Farooque M (2000) Spinal cord compression injury in the mouse: presentation of a model including assessment of motor dysfunction. Acta Neuropathol (Berl) 100:13–22

    Article  CAS  Google Scholar 

  15. Stephanou A, Brar BK, Scarabelli TM et al (2000) Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J Biol Chem 275:10002–10008

    Article  PubMed  CAS  Google Scholar 

  16. Choi YB, Kim YI, Lee KS et al (2004) Protective effect of epigallocatechin gallate on brain damage after transient middle cerebral artery occlusion in rats. Brain Res 1019:47–54

    Article  PubMed  CAS  Google Scholar 

  17. Townsend PA, Scarabelli TM, Pasini E et al (2004) Epigallocatechin-3-gallate inhibits STAT-1 activation and protects cardiac myocytes from ischemia/reperfusion-induced apoptosis. FASEB J 18:1621–1623

    PubMed  CAS  Google Scholar 

  18. Kumar A, Commane M, Flickinger TW et al (1997) Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278:1630–1632

    Article  PubMed  CAS  Google Scholar 

  19. Chin YE, Kitagawa M, Kuida K et al (1997) Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol 17:5328–5337

    PubMed  CAS  Google Scholar 

  20. Schindler C, Shuai K, Prezioso VR et al (1992) Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257:809–813

    Article  PubMed  CAS  Google Scholar 

  21. Olsson T, Kristensson K, Ljungdahl A et al (1989) Gamma-interferon-like immunoreactivity in axotomized rat motor neurons. J Neurosci 9:3870–3875

    PubMed  CAS  Google Scholar 

  22. Kamencic H, Griebel RW, Lyon AW et al (2001) Promoting glutathione synthesis after spinal cord trauma decreases secondary damage and promotes retention of function. FASEB J 15:243–250

    Article  PubMed  CAS  Google Scholar 

  23. Sugawara T, Lewen A, Gasche Y et al (2002) Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release. FASEB J 16:1997–1999

    PubMed  CAS  Google Scholar 

  24. Xu W, Chi L, Xu R et al (2005) Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury. Spinal Cord 43:204–213

    Article  PubMed  CAS  Google Scholar 

  25. Ferrante RJ, Browne SE, Shinobu LA et al (1997) Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 69:2064–2074

    Article  PubMed  CAS  Google Scholar 

  26. Simon AR, Rai U, Fanburg BL et al (1998) Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol 275:C1640–C1652

    PubMed  CAS  Google Scholar 

  27. Gorina R, Sanfeliu C, Galito A et al (2007) Exposure of glia to pro-oxidant agents revealed selective Stat1 activation by H2O2 and Jak2-independent antioxidant features of the Jak2 inhibitor AG490. Glia 55:1313–1324

    Article  PubMed  Google Scholar 

  28. Osuka K, Watanabe Y, Usuda N et al (2010) Oxidative stress activates STAT1 in basilar arteries after subarachnoid hemorrhage. Brain Res 1332:12–19

    Article  PubMed  CAS  Google Scholar 

  29. Suzuki S, Tanaka K, Nogawa S et al (2001) Phosphorylation of signal transducer and activator of transcription-3 (Stat3) after focal cerebral ischemia in rats. Exp Neurol 170:63–71

    Article  PubMed  CAS  Google Scholar 

  30. Wen TC, Peng H, Hata R et al (2001) Induction of phosphorylated-Stat3 following focal cerebral ischemia in mice. Neurosci Lett 303:153–156

    Article  PubMed  CAS  Google Scholar 

  31. Dziennis S, Jia T, Ronnekleiv OK et al (2007) Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection. J Neurosci 27:7268–7274

    Article  PubMed  CAS  Google Scholar 

  32. Yamashita T, Sawamoto K, Suzuki S et al (2005) Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 94:459–468

    Article  PubMed  CAS  Google Scholar 

  33. Xuan YT, Guo Y, Han H et al (2001) An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc Natl Acad Sci U S A 98:9050–9055

    Article  PubMed  CAS  Google Scholar 

  34. Negoro S, Kunisada K, Tone E et al (2000) Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc Res 47:797–805

    Article  PubMed  CAS  Google Scholar 

  35. Hilfiker-Kleiner D, Hilfiker A, Fuchs M et al (2004) Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95:187–195

    Article  PubMed  CAS  Google Scholar 

  36. Xuan YT, Guo Y, Zhu Y et al (2003) Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J Mol Cell Cardiol 35:525–537

    Article  PubMed  CAS  Google Scholar 

  37. Kim EJ, Raval AP, Perez-Pinzon MA (2008) Preconditioning mediated by sublethal oxygen-glucose deprivation-induced cyclooxygenase-2 expression via the signal transducers and activators of transcription 3 phosphorylation. J Cereb Blood Flow Metab 28:1329–1340

    Article  PubMed  CAS  Google Scholar 

  38. Scarabelli TM, Townsend PA, Chen Scarabelli C et al (2008) Amino acid supplementation differentially modulates STAT1 and STAT3 activation in the myocardium exposed to ischemia/reperfusion injury. Am J Cardiol 101:63E–68E

    Article  PubMed  CAS  Google Scholar 

  39. Harada M, Qin Y, Takano H et al (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11:305–311

    Article  PubMed  CAS  Google Scholar 

  40. Zhang X, Shan P, Alam J et al (2005) Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem 280:8714–8721

    Article  PubMed  CAS  Google Scholar 

  41. Wen Z, Zhong Z, Darnell JE Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250

    Article  PubMed  CAS  Google Scholar 

  42. Stephanou A, Scarabelli TM, Brar BK et al (2001) Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. J Biol Chem 276:28340–28347

    Article  PubMed  CAS  Google Scholar 

  43. McCormick J, Barry SP, Sivarajah A et al (2006) Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury. FASEB J 20:2115–2117

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a grant from the Smoking Research Foundation (Y. W.), by the Japan–China Medical Association (Y. W.) and by a Grant-in-Aid for Scientific Research and High Technology Research Centre Project (19-8) (Y. W.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, Aichi Medical University, 21 Yazako, Nagakute, Aichi, 480-1195, Japan

    Koji Osuka, Muneyoshi Yasuda & Masakazu Takayasu

  2. High Technology Research Center, Pharmacology, Showa Pharmaceutical University, 3-3165, Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan

    Yasuo Watanabe

  3. Department of Anatomy II, Fujita Health University School of Medicine, 1-98 Dengakugabo, Kutsukake, Toyoake, Aichi, 470-1192, Japan

    Nobuteru Usuda & Kimie Atsuzawa

  4. Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan

    Chihiro Aoshima & Toshihiko Wakabayashi

Authors
  1. Koji Osuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuo Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuteru Usuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kimie Atsuzawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Muneyoshi Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chihiro Aoshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshihiko Wakabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masakazu Takayasu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuo Watanabe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Osuka, K., Watanabe, Y., Usuda, N. et al. Activation of STAT1 in Neurons Following Spinal Cord Injury in Mice. Neurochem Res 36, 2236–2243 (2011). https://doi.org/10.1007/s11064-011-0547-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0547-6

Keywords

Search

Navigation