Cellular and Molecular Neurobiology

, Volume 27, Issue 7, pp 909–921 | Cite as

Induction of TNF-α by LPS in Schwann Cell is Regulated by MAPK Activation Signals

  • Chun Cheng
  • Yongwei Qin
  • Xiaoyi Shao
  • Haibo Wang
  • Yongjing Gao
  • Mengling Cheng
  • Aiguo ShenEmail author
Original Paper


Mitogen-activated protein kinases (MAPKs) are important mediators of cytokine expression and are critically involved in the immune response. The lipopolysaccharide (LPS) of gram-negative bacteria induces the expression of cytokines and proinflammatory genes via the toll-like receptor 4 (TLR4) signaling pathway in diverse cell types. In vivo, Schwann cells (SCs) at the site of injury may also produce tumor necrosis factor-- α (TNF-α). However, the precise mechanisms of TNF-α synthesis are still not clear. The purpose of the present study was to elucidate the underlying molecular mechanisms in the cultured SCs for its ability to activate the MAPKs and TNF-α gene, in response to LPS. Using enzyme-linked immunosorbent assay (ELISA), it was confirmed that treatment with LPS stimulated the synthesis of TNF-α in a concentration- and time-dependent manner. Intracellular location of TNF-α was detected under confocal microscope. Moreover, LPS activated extracellular signal-regulated kinase (ERK1/2), P38 and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and induced their phosphorylation. LPS-elicited SCs TNF-α production was also drastically suppressed by PD98059 (ERK inhibitor), SB202190 (P38 inhibitor), or SP600125 (SAPK/JNK inhibitor). Additionally, the expression of CD14 and TLR4 was examined by RT–PCR. It was demonstrated that the expression of CD14, TLR4 was crucial for the SCs responses to LPS. In conclusion, the results provide novel mechanisms for the response of SCs to LPS stimulation, through MAPKs signaling pathways.


Lipopolysaccharide Schwann cell Tumor necrosis factor-alpha Mitogen-activated protein kinase 



This work was supported by the National Natural Science Foundation of China (NSFC); grant numbers: 30300099, 30500153, 30770488.


  1. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756PubMedCrossRefGoogle Scholar
  2. Arndt PG, Suzuki N, Avdi NJ, Malcolm KC, Worthen GS (2004) Lipopolysaccharide-induced c-Jun NH2-terminal kinase activation in human neutrophils: role of phosphatidylinositol 3-kinase and Syk-mediated pathways. J Biol Chem 279:10883–10891PubMedCrossRefGoogle Scholar
  3. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF-α promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122PubMedCrossRefGoogle Scholar
  4. Brockes JP, Fields KL, Raff MC (1979) Studies on cultured rat Schwann cells. Establishment of purified populations from cultures of peripheral nerve. Brain Res 165:105–118PubMedCrossRefGoogle Scholar
  5. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T-cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403–411PubMedCrossRefGoogle Scholar
  6. Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I (2005) Estrogen and cytokines production—the possible cause of gender differences in neurological diseases. Curr Pharm Des 11:1017–1030PubMedCrossRefGoogle Scholar
  7. Diks SH, Richel DJ, Peppelenbosch MP (2004) LPS signal transduction: the picture is becoming more complex. Curr Top Med Chem 4:1115–1126PubMedCrossRefGoogle Scholar
  8. Jenner RG, Young RA (2005) Insights into host responses against pathogens from transcriptional profiling. Nat Rev Microbiol 3:281–294PubMedCrossRefGoogle Scholar
  9. Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Huber M, Kalis C, Keck S, Galanos C, Freudenberg M, Beutler B (2005) CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6:565–570PubMedCrossRefGoogle Scholar
  10. Ng V, Zanazzi G, Timpl R, Talts JF, Salzer JL, Brennan PJ, Rambukkana A (2000) Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell 103:511–524PubMedCrossRefGoogle Scholar
  11. Oliveira RB, Ochoa MT, Sieling PA, Rea TH, Rambukkana A, Sarno EN, Modlin RL (2003) Expression of toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect Immun 71:1427–1433PubMedCrossRefGoogle Scholar
  12. Orlikowski D, Chazaud B, Plonquet A, Poron F, Sharshar T, Maison P, Raphael JC, Gherardi RK, Creange A (2003) Monocyte chemoattractant protein 1 and chemokine receptor CCR2 productions in Guillain-Barre syndrome and experimental autoimmune neuritis. J Neuroimmunol 134:118–127PubMedCrossRefGoogle Scholar
  13. Peavy DL, Baughn RE, Musher DM (1978) Strain-dependent cytotoxic effects of endotoxin for mouse peritoneal macrophages. Infect Immun 21:310–319PubMedGoogle Scholar
  14. Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M, Malle E, Schaefer RM, Grone HJ (2005) The matrix component biglycan is proinflammatory and signals through toll-like receptors 4 and 2 in macrophages. J Clin Invest 115:2223–2233PubMedCrossRefGoogle Scholar
  15. Shamash S, Reichert F, Rotshenker S (2002) The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 22:3052–3060PubMedGoogle Scholar
  16. Suzuki S, Singhirunnusorn P, Nakano H, Doi T, Saiki I, Sakurai H (2006) Identification of TNF-alpha-responsive NF-kappaB p65-binding element in the distal promoter of the mouse serine protease inhibitor SerpinE2. FEBS Lett 580:3257–3262PubMedCrossRefGoogle Scholar
  17. Tang X, Marciano DL, Leeman SE, Amar S (2005) LPS induces the interaction of a transcription factor, LPS-induced TNF-alpha factor, and STAT6 (B) with effects on multiple cytokines. Proc Natl Acad Sci USA 102:5132–5137PubMedCrossRefGoogle Scholar
  18. Tang X, Metzger D, Leeman S, Amar S (2006) LPS-induced TNF-alpha factor (LITAF)-deficient mice express reduced LPS-induced cytokine: evidence for LITAF-dependent LPS signaling pathways. Proc Natl Acad Sci USA 103:13777–13782PubMedCrossRefGoogle Scholar
  19. Uematsu S, Akira S (2006) Toll-like receptors and innate immunity. J Mol Med 84:712–725PubMedCrossRefGoogle Scholar
  20. Wagner R, Myers RR (1996) Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves. Neuroscience 73:625–629PubMedCrossRefGoogle Scholar
  21. Yang L, Lindholm K, Konishi Y, Li R, Shen Y (2002) Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J Neurosci 22:3025–3032PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Chun Cheng
    • 1
    • 2
  • Yongwei Qin
    • 3
  • Xiaoyi Shao
    • 2
  • Haibo Wang
    • 2
  • Yongjing Gao
    • 4
  • Mengling Cheng
    • 2
  • Aiguo Shen
    • 1
    Email author
  1. 1.Key Laboratory for Neuroregeneration of JiangSu ProvinceNantong UniversityNantongPR China
  2. 2.Department of Microbiology and Immunology, Medical CollegeNantong UniversityNantongPR China
  3. 3.Department of Parasitology, Medical CollegeNantong UniversityNantongPR China
  4. 4.Institute of Nautical MedicineNantong UniversityNantongPR China

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