Skip to main content

Advertisement

SpringerLink
Log in

Tetrandrine suppresses LPS-induced astrocyte activation via modulating IKKs-IκBα-NF-κB signaling pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Astrocyte activation has been implicated in the pathogenesis of many neurological diseases. These reactive astrocytes are capable of producing a variety of proinflammatory mediators and potentially neurotoxic compounds, such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). In this study, we examined the suppressive effects of Tetrandrine (TET) on astrocyte activation induced by lipopolysaccharide (LPS) in vitro. We found that TET decreased the release of NO, TNF-α, IL-6 and IL-1β in LPS-activated astrocytes. Also mRNA expression levels of inducible nitric oxide synthase (iNOS), macrophage inflammatory protein-1α (MIP-1α) and vascular cell adhesion molecule-1 (VCAM-1) were inhibited in TET pretreated astrocytes. Such suppressive effects might be resulted from the inhibition of nuclear factor kappa B (NF-κB) activation through downregulating IκB kinases (IKKs) phosphoration, which decreased inhibitor of nuclear factor-κB-α (IκBα) phosphoration and degradation. Our results suggest that TET acted to regulate astrocyte activation through inhibiting IKKs-IκBα-NF-κB signaling pathway.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ambrosini E, Aloisi F (2004) Chemokines and glial cells: a complex network in the central nervous system. Neurochem Res 29:1017–1038. doi:10.1023/B:NERE.0000021246.96864.89

    Article  PubMed  CAS  Google Scholar 

  2. Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 37:289–305. doi:10.1016/j.biocel.2004.07.009

    Article  PubMed  CAS  Google Scholar 

  3. Holley JE, Gveric D, Newcombe J, Cuzner ML, Gutowski NJ (2003) Astrocyte characterization in the multiple sclerosis glial scars. Neuropathol Appl Neurobiol 29:434–444. doi:10.1046/j.1365-2990.2003.00491.x

    Article  PubMed  CAS  Google Scholar 

  4. Volterra A, Meldoles J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640. doi:10.1038/nrn1722

    Article  PubMed  CAS  Google Scholar 

  5. Li S, Wang L, Berman MA, Zhang Y, Dorf ME (2006) RNAi screen in mouse astrocytes identifies phosphatases that regulate NF-kappaB signaling. Mol Cell 24:497–509. doi:10.1016/j.molcel.2006.10.015

    Article  PubMed  CAS  Google Scholar 

  6. Bal-Price A, Brown GC (2000) Nitric-oxide-induced necrosis and apoptosis in PC12 cells mediated by mitochondria. J Neurochem 75:1455–1464. doi:10.1046/j.1471-4159.2000.0751455.x

    Article  PubMed  CAS  Google Scholar 

  7. Moynagh PN (2005) The interleukin-1 signaling pathway in astrocytes: a key contributor to inflammation in the brain. J Anat 207:265–269. doi:10.1111/j.1469-7580.2005.00445.x

    Article  PubMed  CAS  Google Scholar 

  8. Gimenez MA, Sim JE, Russell JH (2004) TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation. J Neuroimmunol 151:116–125. doi:10.1016/j.jneuroim.2004.02.012

    Article  PubMed  CAS  Google Scholar 

  9. Jang BC, Lim KJ, Paik JH, Cho JW, Baek WK, Suh MH et al (2004) Tetrandrine-induced apoptosis is mediated by activation of caspases and PKC-delta in U937 cells. Biochem Pharmacol 67:1819–1829. doi:10.1016/j.bcp.2004.01.018

    Article  PubMed  CAS  Google Scholar 

  10. Wu SJ, Ng LT (2007) Tetrandrine inhibits proinflammatory Cytokines, iNOS and COX-2 expression in human monocytic cells. Biol Pharm Bull 30:59–62. doi:10.1248/bpb.30.59

    Article  PubMed  CAS  Google Scholar 

  11. Chen F, Sun S, Kuhn DC, Lu Y, Gaydos LJ, Shi X et al (1997) Tetrandrine inhibits signal-induced NF-kappa B activation in rat alveolar macrophages. Biochem Biophys Res Commun 231:99–102. doi:10.1006/bbrc.1997.6057

    Article  PubMed  CAS  Google Scholar 

  12. Ho LJ, Juan TY, Chao P, Wu WL, Chang DM, Chang SY et al (2004) Plant alkaloid tetrandrine downregulates IkappaBalpha kinases-IkappaBalpha-NF-kappaB signaling pathway in human peripheral blood T cell. Br J Pharmacol 143:919–927. doi:10.1038/sj.bjp.0706000

    Article  PubMed  CAS  Google Scholar 

  13. Ho LJ, Chang DM, Lee TC, Chang ML, Lai JH (1999) Plant alkaloid Tetrandrine downregulates protein kinase C-dependent signaling pathway in T cells. Eur J Pharmacol 367:389–398. doi:10.1016/S0014-2999(98)00941-8

    Article  PubMed  CAS  Google Scholar 

  14. Xue Y, Wang Y, Feng DC, Xiao BG, Xu LY (2008) Tetrandrine suppresses lipopolysaccharide-induced microglial activation by inhibiting NF-kappaB pathway. Acta Pharmacol Sin 29:245–251. doi:10.1111/j.1745-7254.2008.00734.x

    Article  PubMed  CAS  Google Scholar 

  15. Chung IY, Benveniste EN (1990) Tumor necrosis factor-alpha production by astrocytes: induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol 144:2999–3007

    PubMed  CAS  Google Scholar 

  16. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765. doi:10.1126/science.1088417

    Article  PubMed  CAS  Google Scholar 

  17. Xu LY, Yang JS, Xiao BG (2002) TGF-beta1-conditioned glial cell-derived dendritic cells inhibit expansion of MBP-reactive T cells in vitro. Neuroreport 13:35–39. doi:10.1097/00001756-200201210-00012

    Article  PubMed  CAS  Google Scholar 

  18. Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190. doi:10.1002/glia.1107

    Article  PubMed  CAS  Google Scholar 

  19. Karin M, Lin A (2002) NF-κB at the crossroads of life and death. Nat Immunol 3:221–227. doi:10.1038/ni0302-221

    Article  PubMed  CAS  Google Scholar 

  20. Ghosh S, Karin M (2002) Missing pieces in the NF-κB puzzle. Cell 109(Suppl):S81–S96. doi:10.1016/S0092-8674(02)00703-1

    Article  PubMed  CAS  Google Scholar 

  21. van Loo G, De Lorenzi R, Schmidt H, Huth M, Mildner A, Schmidt-Supprian M et al (2006) Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol 7:954–961. doi:10.1038/ni1372

    Article  PubMed  Google Scholar 

  22. Maragakis NJ, Rothstein JD (2006) Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689. doi:10.1038/ncpneuro0355

    Article  PubMed  CAS  Google Scholar 

  23. Pahan K, Sheikh FG, Khan M, Namboodiri AM, Singh I (1998) Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. J Biol Chem 273:2591–2600. doi:10.1074/jbc.273.5.2591

    Article  PubMed  CAS  Google Scholar 

  24. Satoh J, Kastrukoff LF, Kim SU (1991) Cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1) in cultured human oligodendrocytes and astrocytes. J Neuropathol Exp Neurol 50:215–226. doi:10.1097/00005072-199105000-00004

    Article  PubMed  CAS  Google Scholar 

  25. Hayashi M, Luo Y, Laning J, Strieter RM, Dorf ME (1995) Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol 60:143–150. doi:10.1016/0165-5728(95)00064-9

    Article  PubMed  CAS  Google Scholar 

  26. Hurwitz AA, Lyman WD, Berman JW (1995) Tumor necrosis factor alpha and transforming growth factor beta upregulate astrocyte expression of monocyte chemoattractant protein-1. J Neuroimmunol 57:193–198. doi:10.1016/0165-5728(95)00011-P

    Article  PubMed  CAS  Google Scholar 

  27. Louis JC, Magal E, Takayama S, Varon S (1993) CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689–692. doi:10.1126/science.8430320

    Article  PubMed  CAS  Google Scholar 

  28. Klein MA, Moller JC, Jones LL, Bluethmann H, Kreutzberg GW, Raivich G (1997) Impaired neuroglial activation in interleukin-6-deficient mice. Glia 19:227–233. doi:10.1002/(SICI)1098-1136(199703)19:3 < 227::AID-GLIA5 > 3.0.CO;2-W

    Article  PubMed  CAS  Google Scholar 

  29. Abbott NJ (2002) Astrocyte–endothelial interactions and blood-brain barrier permeability. J Anat 200:629–638. doi:10.1046/j.1469-7580.2002.00064.x

    Article  PubMed  CAS  Google Scholar 

  30. Ajuebor MN, Das AM, Virag L, Szabo C, Perretti M (1999) Regulation of macrophage inflammatory protein-1 alpha expression and function by endogenous interleukin-10 in a model of acute inflammation. Biochem Biophys Res Commun 255:279–282. doi:10.1006/bbrc.1999.0196

    Article  PubMed  CAS  Google Scholar 

  31. Olson TS, Ley K (2002) Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol 283:R7–R28

    PubMed  CAS  Google Scholar 

  32. Shiao YJ, Lin YL, Sun YH, Chi CW, Chen CF, Wang CN (2005) Falcarindiol impairs the expression of inducible nitric oxide synthase by abrogating the activation of IKK and JAK in rat primary astrocytes. Br J Pharmacol 144:42–51. doi:10.1038/sj.bjp.0706022

    Article  PubMed  CAS  Google Scholar 

  33. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S et al (2005) Inhibition of astroglial nuclear factor kappa B reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156. doi:10.1084/jem.20041918

    Article  PubMed  CAS  Google Scholar 

  34. Zhang W, Potrovita I, Tarabin V, Herrmann O, Beer V, Weih F et al (2005) Neuronal activation of NF-kappaB contributes to cell death i/n cerebral ischemia. J Cereb Blood Flow Metab 25:30–40. doi:10.1038/sj.jcbfm.9600004

    Article  PubMed  Google Scholar 

  35. Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18:1633–1641

    PubMed  CAS  Google Scholar 

  36. Schumann RR, Pfeil D, Freyer D, Buerger W, Lamping N, Kirschning CJ et al (1998) Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. Glia 22:295–305. doi:10.1002/(SICI)1098-1136(199803)22:3 < 295::AID-GLIA8 > 3.0.CO;2-4

    Article  PubMed  CAS  Google Scholar 

  37. Sun LL, Cheng C, Liu HO, Shen CC, Xiao F, Qin J et al (2007) Src suppressed C kinase substrate regulates the lipopolysaccharide-induced TNF-alpha biosynthesis in rat astrocytes. J Mol Neurosci 32:16–24. doi:10.1007/s12031-007-0003-x

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Science and Technology Commission of Shanghai Municipality (04DZ14902), Shanghai Leading Academic Discipline Project (T0206), and the Knowledge Innovation Program of the Chinese Academy of Sciences (J0171-1905).

Author information

Authors and Affiliations

  1. Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Shu-Ting Lin, Ying Wang, Yang Xue & Ling-Yun Xu

  2. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiaotong University School of Medicine, Building I Room 308, 225 South Chongqing Road, Shanghai, 200025, People’s Republic of China

    De-Chun Feng, Yan Xu & Ling-Yun Xu

Authors
  1. Shu-Ting Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. De-Chun Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ling-Yun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ling-Yun Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, ST., Wang, Y., Xue, Y. et al. Tetrandrine suppresses LPS-induced astrocyte activation via modulating IKKs-IκBα-NF-κB signaling pathway. Mol Cell Biochem 315, 41–49 (2008). https://doi.org/10.1007/s11010-008-9787-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-008-9787-4

Keywords

Search

Navigation