Skip to main content

Advertisement

SpringerLink
Log in

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Mediates p38 Mitogen-Activated Protein Kinase Activation and Signal Transduction in Peripheral Blood Mononuclear Cells from Patients with Lupus Nephritis

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Forty-two patients with systemic lupus erythematosus (SLE), including 26 patients with renal damage and 16 without, and 20 healthy controls were included in the study. The isolated peripheral blood mononuclear cells (PBMCs) were treated with a p38 inhibitor (SB203580) or anti-tumor necrosis factor-like weak inducer of apoptosis (TWEAK) mAb, with or without phytohemagglutinin/phorbol myristate acetate (PHA/PMA) stimulation. Western blot experiments were used to evaluate the protein expression of TWEAK and p38 MAPK in PBMCs .Next, the contents of interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) in the supernatant were measured by ELISA. The results showed that expression of TWEAK protein in PBMCs from lupus nephritis patients was significantly higher than that from SLE patients without renal damage and healthy controls. PHA/PMA simulation could upregulate the productions of TWEAK and p-p38MAPK in PBMCs from patients with SLE. Anti-TWEAK mAb treatment downregulated both TWEAK and p-p38 MAPK expression in PBMCs, as well as IL-10 and MCP-1 in the supernatant; SB203580 had the same effect on cytokine production in PBMC, but had no effect on the expression of TWEAK. Our results suggested that TWEAK–p38 MAPK–IL-10, MCP-1 signaling pathway in PBMC played an important pathogenic role in lupus nephritis.

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

Similar content being viewed by others

Abbreviations

DAPI:

4′,6-Diamidino-2-phenylindole

SLE:

Systemic lupus erythematosus

LN:

Lupus nephritis

TWEAK:

Tumor necrosis factor-like weak inducer of apoptosis

p38 MAPK:

P38 mitogen- activated protein kinase

IL-10:

Interleukin-10

MCP-1:

Monocyte chemoattractant protein-1

TNFRSF:

Tumor Necrosis Factor receptor superfamily

NRSLE:

SLE patients without renal involvement

PBMC:

Peripheral blood mononuclear cell

References

  1. Namjou, B., J. Kilpatrick, and J.B. Harley. 2007. Genetics of clinical expression in SLE. Autoimmunity 40: 602–612.

    Article  PubMed  CAS  Google Scholar 

  2. Ka, S.M., C.W. Cheng, H.A. Shui, et al. 2007. Mesangial cells of lupus-prone mice are sensitive to chemokine production. Arthritis Research & Therapy 9: R67.

    Article  Google Scholar 

  3. Tabibian-Keissar, H., N.S. Zuckerman, M. Barak, et al. 2008. B-cell clonal diversification and gut-lymph node trafficking in ulcerative colitis revealed using lineage tree analysis. European Journal of Immunology 38: 2600–2609.

    Article  PubMed  CAS  Google Scholar 

  4. Chan, O., and M.J. Shlomchik. 1998. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. Journal of Immunology 160: 51–59.

    CAS  Google Scholar 

  5. Schwartz, N., J.S. Michaelson, and C. Putterman. 2007. Lipocalin-2, TWEAK, and other cytokines as urinary biomarkers for lupus nephritis. Annals of the New York Academy of Sciences 1109: 265–274.

    Article  PubMed  CAS  Google Scholar 

  6. Li, Y., M. Tucci, S. Narain, et al. 2006. Urinary biomarkers in lupus nephritis. Autoimmunity Reviews 5: 383–388.

    Article  PubMed  CAS  Google Scholar 

  7. Goulvestre, C., F. Batteux, and J. Charreire. 2002. Chemokines modulate experimental autoimmune thyroiditis through attraction of autoreactive or regulatory T cells. European Journal of Immunology 32: 3435–3442.

    PubMed  CAS  Google Scholar 

  8. Marks, S.D., S.J. Williams, K. Tullus, et al. 2008. Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. Nephrology, Dialysis, Transplantation 23: 3521–3526.

    Article  PubMed  CAS  Google Scholar 

  9. Zhao, Z., L.C. Burkly, S. Campbell, et al. 2007. TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. Journal of Immunology 179: 7949–7958.

    CAS  Google Scholar 

  10. Chi, H., S.P. Barry, R.J. Roth, et al. 2006. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proceedings of the National Academy of Sciences of the United States of America 103(7): 2274–2279.

    Article  PubMed  CAS  Google Scholar 

  11. Iwata, Y., T. Wada, K. Furuichi, et al. 2003. p38 Mitogen-activated protein kinase contributes to autoimmune renal injury in MRL-Fas lpr mice. Journal of the American Society of Nephrology 14(1): 57–67.

    Article  PubMed  CAS  Google Scholar 

  12. Wang, X.S., K. Diener, C.L. Manthey, et al. 1997. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. Journal of Biological Chemistry 272: 23668–23674.

    Article  PubMed  CAS  Google Scholar 

  13. Herlaar, E., and Z. Brown. 1999. p38 MAPK signaling cascades in inflammatory disease. Mol Medicine Today 5: 439–447.

    Article  CAS  Google Scholar 

  14. Wang, X., and Y. Liu. 2007. Regulation of innate immune response by MAP kinase phosphatase-1. Cellular Signalling 19: 1372–1382.

    Article  PubMed  CAS  Google Scholar 

  15. Li, L., S.F. Chen, and Y. Liu. 2009. MAP kinase phosphatase-1, a critical negative regulator of the innate immune response. International Journal of Clinical and Experimental Medicine 2: 48–67.

    PubMed  Google Scholar 

  16. Cook, R., C.C. Wu, Y.J. Kang, et al. 2007. The role of the p38 pathway in adaptive immunity. Cellular & Molecular Immunology 4: 253–259.

    CAS  Google Scholar 

  17. Kim, J.M., J.M. White, A.S. Shaw, et al. 2005. MAPK p38 alpha is dispensable for lymphocyte development and proliferation. Journal of Immunology 174: 1239–1244.

    CAS  Google Scholar 

  18. Li, H., A. Mittal, P.K. Paul, et al. 2009. Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of nuclear factor inducing kinase and p38 mitogen-activated protein kinase, a potential role of MMP-9 in myopathy. The Journal of Biological Chemistry 284: 4439–4450.

    Article  PubMed  CAS  Google Scholar 

  19. Blanco-Colio, L.M., J.L. Martin-Ventura, B. Munoz-Garcia, et al. 2007. TWEAK and Fn14. New players in the pathogenesis of atherosclerosis. Frontiers in Bioscience 12: 3648–3655.

    Article  PubMed  CAS  Google Scholar 

  20. Winkles, J.A., N.L. Tran, and M.E. Berens. 2006. TWEAK and Fn14: new molecular targets for cancer therapy? Cancer Letters 235: 11–17.

    Article  PubMed  CAS  Google Scholar 

  21. Leng, R.X., H.F. Pan, W.Z. Qin, et al. 2010. TWEAK as a target for therapy in systemic lupus erythematosus. Molecular Biology Reports 38: 587–592.

    Article  PubMed  Google Scholar 

  22. Clark, J., P. Vagenas, M. Panesar, et al. 2005. What does tumour necrosis factor excess do to the immune system long term? Annals of the Rheumatic Diseases 64(Suppl 4): 70–76.

    Google Scholar 

  23. Cheema, I.R., C. Hermann, S. Postell, et al. 2000. Effect of chronic excess of tumour necrosis factor-alpha on contractile proteins in rat skeletal muscle. Cytobios 103: 169–176.

    PubMed  CAS  Google Scholar 

  24. Campbell, S., J. Michaelson, L. Burkly, et al. 2004. The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Frontiers in Bioscience 9: 2273–2284.

    Article  PubMed  CAS  Google Scholar 

  25. Kollias, G., and D. Kontoyiannis. 2002. Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. Cytokine & Growth Factor Reviews 13: 315–321.

    Article  CAS  Google Scholar 

  26. Kollias, G., D. Kontoyiannis, E. Douni, et al. 2002. The role of TNF/TNFR in organ-specific and systemic autoimmunity: implications for the design of optimized ‘anti-TNF’ therapies. Current Directions in Autoimmunity 5: 30–50.

    Article  PubMed  CAS  Google Scholar 

  27. Suvannavejh, G.C., H.O. Lee, J. Padilla, et al. 2000. Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG(35–55)-induced experimental autoimmune encephalomyelitis. Cellular Immunology 205: 24–33.

    Article  PubMed  CAS  Google Scholar 

  28. Ju, S.T., K. Matsui, and M. Ozdemirli. 1999. Molecular and cellular mechanisms regulating T and B cell apoptosis through Fas/FasL interaction. International Reviews of Immunology 18: 485–513.

    Article  PubMed  CAS  Google Scholar 

  29. Wong, B., and Y. Choi. 1997. Pathways leading to cell death in T cells. Current Opinion in Immunology 9: 358–364.

    Article  PubMed  CAS  Google Scholar 

  30. Qin, H.Y., P. Chaturvedi, and B. Singh. 2004. In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-gamma/TNF-alpha. International Immunology 16: 1723–1732.

    Article  PubMed  CAS  Google Scholar 

  31. Mueller, A.M., X. Pedre, I. Kleiter, et al. 2005. Targeting fibroblast growth factor-inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis. Journal of Neuroimmunology 159: 55–65.

    Article  PubMed  CAS  Google Scholar 

  32. Kaplan, M.J., E.E. Lewis, E.A. Shelden, et al. 2002. The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells. Journal of Immunology 169: 6020–6029.

    CAS  Google Scholar 

  33. Schwartz, N., L. Su, L.C. Burkly, et al. 2006. Urinary TWEAK and the activity of lupus nephritis. Journal of Autoimmunity 27: 242–250.

    Article  PubMed  CAS  Google Scholar 

  34. Molano, A., P. Lakhani, A. Aran, et al. 2009. TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis. Immunology Letters 125: 119–128.

    Article  PubMed  CAS  Google Scholar 

  35. Xu, H., A. Okamoto, J. Ichikawa, et al. 2004. TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce IL-8 and GM-CSF. Biochemical and Biophysical Research Communications 318: 422–427.

    Article  PubMed  CAS  Google Scholar 

  36. Gao, H.X., S.R. Campbell, L.C. Burkly, et al. 2009. TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. Cytokine 46: 24–35.

    Article  PubMed  CAS  Google Scholar 

  37. Lichtner, M., C. Maranon, P.O. Vidalain, et al. 2004. HIV type 1-infected dendritic cells induce apoptotic death in infected and uninfected primary CD4 T lymphocytes. AIDS Research and Human Retroviruses 20: 175–182.

    Article  PubMed  CAS  Google Scholar 

  38. Campbell, S., L.C. Burkly, H.X. Gao, et al. 2006. Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. Journal of Immunology 176: 1889–1898.

    CAS  Google Scholar 

  39. Jakubowski, A., B. Browning, M. Lukashev, et al. 2002. Dual role for TWEAK in angiogenic regulation. Journal of Cell Science 115: 267–274.

    PubMed  CAS  Google Scholar 

  40. Miyagawa, H., M. Yamai, D. Sakaguchi, et al. 2008. Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus. Rheumatology (Oxford, England) 47: 158–164.

    Article  CAS  Google Scholar 

  41. Chicheportiche, Y., L. Fossati-Jimack, S. Moll, et al. 2000. Down-regulated expression of TWEAK mRNA in acute and chronic inflammatory pathologies. Biochemical and Biophysical Research Communications 279: 162–165.

    Article  PubMed  CAS  Google Scholar 

  42. Baxter, F.O., P.J. Came, K. Abell, et al. 2006. IKKbeta/2 induces TWEAK and apoptosis in mammary epithelial cells. Development 133: 3485–3494.

    Article  PubMed  CAS  Google Scholar 

  43. Desplat-Jego, S., R. Creidy, S. Varriale, et al. 2005. Anti-TWEAK monoclonal antibodies reduce immune cell infiltration in the central nervous system and severity of experimental autoimmune encephalomyelitis. Clinical Immunology 117: 15–23.

    Article  PubMed  CAS  Google Scholar 

  44. Zheng, T.S., and L.C. Burkly. 2008. No end in site: TWEAK/Fn14 activation and autoimmunity associated-end-organ pathologies. Journal of Leukocyte Biology 84: 338–347.

    Article  PubMed  CAS  Google Scholar 

  45. Winkles, J.A. 2008. The TWEAK-Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting. Nature Reviews. Drug Discovery 7: 411–425.

    Article  PubMed  CAS  Google Scholar 

  46. Pradet-Balade, B., J.P. Medema, M. Lopez-Fraga, et al. 2002. An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein. EMBO Journal 21: 5711–5720.

    Article  PubMed  CAS  Google Scholar 

  47. Desplat-Jego, S., L. Feuillet, R. Creidy, et al. 2009. TWEAK is expressed at the cell surface of monocytes during multiple sclerosis. Journal of Leukocyte Biology 85: 132–135.

    Article  PubMed  CAS  Google Scholar 

  48. Nakayama, M., N. Kayagaki, N. Yamaguchi, et al. 2000. Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity. The Journal of Experimental Medicine 192: 1373–1380.

    Article  PubMed  CAS  Google Scholar 

  49. Kaplan, M.J., D. Ray, R.R. Mo, et al. 2000. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. Journal of Immunology 164: 2897–2904.

    CAS  Google Scholar 

  50. Desplat-Je go, S., L. Feuillet, R. Creidy, et al. 2009. TWEAK is expressed at the cell surface of monocytes during multiple sclerosis. Journal of Leukocyte Biology 85: 132–135.

    Article  CAS  Google Scholar 

  51. Chan, F.K., and M.J. Lenardo. 2002. Tumor necrosis factor family ligands and receptors in the immune system: targets for future pharmaceuticals. Drug News & Perspectives 15: 483–490.

    Article  CAS  Google Scholar 

  52. Trouche, N., S. Wieckowski, W. Sun, et al. 2007. Small multivalent architectures mimicking homotrimers of the TNF superfamily member CD40L: delineating the relationship between structure and effector function. Journal of the American Chemical Society 129: 13480–13492.

    Article  PubMed  CAS  Google Scholar 

  53. Idriss, H.T., and J.H. Naismith. 2000. TNF alpha and the TNF receptor superfamily: structure–function relationship(s). Microscopy Research and Technique 50: 184–195.

    Article  PubMed  CAS  Google Scholar 

  54. Yamana, J., L. Santos, and E. Morand. 2009. Enhanced induction of LPS-induced fibroblast MCP-1 by interferon-gamma: involvement of JNK and MAPK phosphatase-1. Cellular Immunology 255: 26–32.

    Article  PubMed  CAS  Google Scholar 

  55. Martin, M., R.E. Schifferle, N. Cuesta, et al. 2003. Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. Journal of Immunology 171: 717–725.

    CAS  Google Scholar 

  56. Richardson, C.E., T. Kooistra, and D.H. Kim. 2010. An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463: 1092–1095.

    Article  PubMed  CAS  Google Scholar 

  57. Ruland, J. 2008. CARD9 signaling in the innate immune response. Annals of the New York Academy of Sciences 1143: 35–44.

    Article  PubMed  CAS  Google Scholar 

  58. Thornton, T.M., and M. Rincon. 2009. Non-classical p38 map kinase functions: cell cycle checkpoints and survival. International Journal of Biological Sciences 5: 44–51.

    Article  PubMed  CAS  Google Scholar 

  59. Colombara, M., V. Antonini, A.P. Riviera, et al. 2005. Constitutive activation of p38 and ERK1/2 MAPKs in epithelial cells of myasthenic thymus leads to IL-6 and RANTES overexpression: effects on survival and migration of peripheral T and B cells. Journal of Immunology 175: 7021–7028.

    CAS  Google Scholar 

  60. Khiem, D., J.G. Cyster, J.J. Schwarz, et al. 2008. A p38 MAPK-MEF2C pathway regulates B-cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 105: 17067–17072.

    Article  PubMed  CAS  Google Scholar 

  61. Alvarado-Kristensson, M., and T. Andersson. 2005. Protein phosphatase 2A regulates apoptosis in neutrophils by dephosphorylating both p38 MAPK and its substrate caspase 3. Journal of Biological Chemistry 280: 6238–62344.

    Article  PubMed  CAS  Google Scholar 

  62. Stambe, C., D.J. Nikolic-Paterson, P.A. Hill, et al. 2004. p38 Mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: correlation with renal injury. Journal of the American Society of Nephrology 15: 326–336.

    Article  PubMed  CAS  Google Scholar 

  63. Ohashi, R., T. Nakagawa, S. Watanabe, et al. 2004. Inhibition of p38 mitogen-activated protein kinase augments progression of remnant kidney model by activating the ERK pathway. American Journal of Pathology 164: 477–485.

    Article  PubMed  CAS  Google Scholar 

  64. Sallusto, F., C.R. Mackay, and A. Lanzavecchia. 2000. The role of chemokine receptors in primary, effector, and memory immune responses. Annual Review of Immunology 18: 593–620.

    Article  PubMed  CAS  Google Scholar 

  65. Nagasawa, M., Z. Yi, S. Imashuku, et al. 2008. Soluble TWEAK is markedly elevated in hemophagocytic lymphohistiocytosis. American Journal of Hematology 83: 222–225.

    Article  PubMed  CAS  Google Scholar 

  66. Garcia, G.E., Y. Xia, J. Harrison, et al. 2003. Mononuclear cell-infiltrate inhibition by blocking macrophage-derived chemokine results in attenuation of developing crescentic glomerulonephritis. American Journal of Pathology 162: 1061–1073.

    Article  PubMed  CAS  Google Scholar 

  67. Marks, S.D., S.J. Williams, and K. Tullus. 2008. Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. Nephrology, Dialysis, Transplantation 23: 3521–3526.

    Article  PubMed  CAS  Google Scholar 

  68. Shimizu, S., H. Nakashima, K. Masutani, et al. 2004. Anti-monocyte chemoattractant protein-1 gene therapy attenuates nephritis in MRL/lpr mice. Rheumatology (Oxford, England) 43: 1121–1128.

    Article  CAS  Google Scholar 

  69. Ishida, H., T. Muchamuel, S. Sakaguchi, et al. 1994. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. The Journal of Experimental Medicine 179: 305–310.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Rheumatology and Immunology, The Second Affiliated Hospital of Suzhou University, Suzhou, China

    Liu Zhi-Chun

  2. Department of Nephrology, Xiangya Hospital, Central South University, Xiangya Road No.87, Changsha, Hunan, 410008, People’s Republic of China

    Zhou Qiao-Ling, Li Xiao-Zhao & Tang Rong

  3. Department of Biological Science & Engineering, Hebei Technology University, Shijiazhuang, China

    Liu Zhi-Qin

  4. Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, China

    Zuo Xiao-xia

Authors
  1. Liu Zhi-Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhou Qiao-Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liu Zhi-Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Xiao-Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zuo Xiao-xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tang Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhou Qiao-Ling.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhi-Chun, L., Qiao-Ling, Z., Zhi-Qin, L. et al. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Mediates p38 Mitogen-Activated Protein Kinase Activation and Signal Transduction in Peripheral Blood Mononuclear Cells from Patients with Lupus Nephritis. Inflammation 35, 935–943 (2012). https://doi.org/10.1007/s10753-011-9396-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-011-9396-3

KEY WORDS

Search

Navigation