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RETRACTED ARTICLE: Purine anti-metabolite attenuates nuclear factor κB and related pro-inflammatory cytokines in experimental vasospasm

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This article was retracted on 11 January 2024

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Abstract

Background

Increased nuclear factor κB (NF-κB) bioexpression, as well as TNF-α, IL-1β and IL-6 levels, were observed after aneurysmal subarachnoid hemorrhage (SAH). It is of interest to investigate the effect of 6-mercaptopurine (6-mp) on cytokines/NF-κB in this SAH model.

Materials and methods

A rodent double-hemorrhage SAH model was employed. Serum and cerebrospinal fluid (CSF) samples were collected to examine IL-1, IL-6 and TNF-α levels. NF-κB subunit p65 and its inhibitor of nuclear factor κB (IκB) were examined (by Western blot). TNF-α was used to induce the phosphorylation of IκB in the presence or absence of 6-mp.

Results

Nuclear NF-κB subunit p65/IκB kinase in the basilar artery was over-expressed, and cytokines was notably increased in the SAH groups, compared with the controls (P < 0.01). In the 6-mp SAH group, obvious reduction was observed in NF-κB subunit p65 (nuclei) (P < 0.01). Treatment with 6-mp significantly reduced IL-1β and TNF-α levels to those of the healthy control. 6-Mercaptopurine also significantly increased the level of IκB in the TNF-α-stimulated SAH rats.

Conclusions

Through inhibiting IκB bioexpression, 6-mp decreases NF-κB-related IL-1β, IL-6, and TNF-α in the presence of SAH. The study suggests 6-mp exerts vascular anti-inflammatory properties through inhibiting IκB kinase and subsequently blocks bio-activation of NF-κB and related cytokines, which may contribute to its antivasospastic effect in animals subjected to SAH.

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References

  1. Aihara Y, Kasuya H, Onda H, Hori T, Takeda J (2001) Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage. Stroke 32:212–217

    Article  CAS  PubMed  Google Scholar 

  2. Asai D, Tsuchiya A, Kang JH, Kawamura K, Oishi J, Mori T, Niidome T, Shoji Y, Nakashima H, Katayama Y (2009) Inflammatory cell-specific transgene expression system responding to Ikappa-B kinase beta activation. J Gene Med 11(7):624–632

    Article  CAS  PubMed  Google Scholar 

  3. Bäck M, Bu DX, Bränström R, Sheikine Y, Yan ZQ, Hansson GK (2005) Leukotriene B4 signaling through NF-κB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intima hyperplasia. Proc Natl Acad Sci USA 102(48):17501–17506

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (2004) A physical and functional map of the human TNF-α/NF-κB signal transduction pathway. Nat Cell Biol 6:97–105

    Article  CAS  PubMed  Google Scholar 

  5. Chang CZ, Lin CL, Kassel NF, Kwan AL, Howng SL (2010) 6-Mercaptopurine attenuates adhesive molecules in experimental vasospasm. Acta Neurochir (Wien) 152(5):861–867

    Article  PubMed  Google Scholar 

  6. Clatterbuck RE, Gailloud P, Ogata L, Gebremariam A, Dietsch GN, Murphy KJ, Tamargo RJ (2003) Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates. J Neurosurg 99:376–382

    Article  CAS  PubMed  Google Scholar 

  7. Dalchau R, Kirkley J, Fabre JW (1980) Monoclonal antibody to a human leukocyte-specific membrane glycoprotein probably homologous to the leukocyte-common (L-C) antigen of the rat. Eur J Immunol 10:737–744

    Article  CAS  PubMed  Google Scholar 

  8. Dauletbaev N, Lam J, Eklove D, Iskandar M, Lands LC (2010) Ibuprofen modulates NF-kB activity but not IL-8 production in cystic fibrosis respiratory epithelial cells. Respiration 79(3):234–242

    Article  CAS  PubMed  Google Scholar 

  9. Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, Kassell NF, Lee KS (2003) Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 53:123–135

    Article  PubMed  Google Scholar 

  10. Fitzpatrick SF, Tambuwala MM, Bruning U, Schaible B, Scholz CC, Byrne A, O’Connor A, Gallagher WM, Lenihan CR, Garvey JF, Howell K, Fallon PG, Cummins EP, Taylor CT (2011) An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol 186(2):1091–1096

    Article  CAS  PubMed  Google Scholar 

  11. Frazier JL, Pradilla G, Wang PP, Tamargo RJ (2004) Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage. J Neurosurg 101(1):93–98

    Article  CAS  PubMed  Google Scholar 

  12. Galor A, Jabs DA, Leder HA, Kedhar SR, Dunn JP, Peters GB 3rd, Thorne JE (2008) Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology 115:1826–1832

    Article  PubMed  Google Scholar 

  13. Garland JM, Rudin C (1998) Cytochrome c induces caspase-dependent apoptosis in intact hematopoietic cells and overrides apoptosis suppression mediated by bcl-1, growth factor signaling, MAP-kinase-kinase, and malignant change. Blood 92:1235–1246

    Article  CAS  PubMed  Google Scholar 

  14. Hansen-Schwartz J, Ansar S, Edvinsson L (2008) Cerebral vasoconstriction after subarachnoid hemorrhage–role of changes in vascular receptor phenotype. Front Biosci 13:2160–2164

    Article  CAS  PubMed  Google Scholar 

  15. Hayes AL, Smith C, Foxwell BM, Brennan FM (1999) CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-kappaB-independent. J Biol Chem 274(47):33455–33461

    Article  CAS  PubMed  Google Scholar 

  16. Kim JY, Morgan M, Kim DG, Lee JY, Bai L, Lin Y, Liu ZG, Kim YS (2011) TNF{α}-induced noncanonical NF-{κ}B activation is attenuated by RIP1 through stabilization of TRAF2. J Cell Sci 124(4):647–656

    Article  CAS  PubMed  Google Scholar 

  17. Kolias AG, Sen J, Belli A (2009) Pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage: putative mechanisms and novel approaches. J Neurosci Res 87(1):1–11

    Article  CAS  PubMed  Google Scholar 

  18. Kubo Y, Ogasawara K, Kakino S, Kashimura H, Tomitsuka N, Sugawara A, Ogawa A (2008) Serum inflammatory adhesion molecules and high-sensitivity C-reactive protein correlates with delayed ischemic neurologic deficits after subarachnoid hemorrhage. Surg Neurol 69(6):592–596

    Article  PubMed  Google Scholar 

  19. Lin CL, Kwan AL, Dumont AS, Su YF, Kassell NF, Wang CJ, Wu SC, Kuo CL, Huang CS, Jeng AY, Liu CS (2007) Attenuation of experimental subarachnoid hemorrhage-induced increases in circulating intercellular adhesion molecule-1 and cerebral vasospasm by the endothelin-converting enzyme inhibitor CGS 26303. J Neurosurg 106(3):442–448

    Article  PubMed  Google Scholar 

  20. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-∆∆C(T) method. Methods 25:402–409

    Article  CAS  PubMed  Google Scholar 

  21. Maruyama K, Tsukada T, Ohkura N, Bandoh S, Hosono T, Yamaguchi K (1998) The NGFI-B subfamily of the nuclear receptor superfamily. Int J Oncol 12(6):1237–1243

    CAS  PubMed  Google Scholar 

  22. Naseri M, Moazzeni SM, Pourfathollah AA (2007) APAAP complex: production and usage in immunocytochemical and immunohistochemical staining. Hum Antibodies 16(3–4):107–115

    CAS  PubMed  Google Scholar 

  23. Ordentlich P, Yan Y, Zhou S, Heyman RA (2003) Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem 278(27):24791–24799

    Article  CAS  PubMed  Google Scholar 

  24. Pawlinski R, Pedersen B, Kehrle B, Aird WC, Frank RD, Guha M, Mackman N (2003) Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model. Blood 101:3940–3947

    Article  CAS  PubMed  Google Scholar 

  25. Provencio JJ, Vora N (2005) Subarachnoid hemorrhage and inflammation: bench to bedside and back. Semin Neurol 25(4):435–444

    Article  PubMed  Google Scholar 

  26. Sánchez E, Singru PS, Wittmann G, Nouriel SS, Barrett P, Fekete C, Lechan RM (2010) Contribution of TNF-alpha and nuclear factor-kappa B signaling to type 2 iodothyronine deiodinase activation in the mediobasal hypothalamus after lipopolysaccharide administration. Endocrinology 151(8):3827–3835

    Article  PubMed  PubMed Central  Google Scholar 

  27. Shih HC, Lin CL, Lee TY, Lee WS, Hsu C (2006) 17beta-Estradiol inhibits subarachnoid hemorrhage-induced inducible nitric oxide synthase gene expression by interfering with the nuclear factor kappa B transactivation. Stroke 37(12):3025–3031

    Article  CAS  PubMed  Google Scholar 

  28. Stet EH, De Abreu RA, Bökkerink JP, Lambooy LH, Vogels-Mentink TM, Keizer-Garritsen JJ, Trijbels FJ (1995) Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine. Biochem Pharmacol 49:49–56

    Article  CAS  PubMed  Google Scholar 

  29. Sue SC, Alverdi V, Komives EA, Dyson HJ (2011) Detection of a ternary complex of NF-{κ}B and I{κ}B{α} with DNA provides insights into how I{κ}B{α} removes NF-{κ}B from transcription sites. Proc Natl Acad Sci U S A 108(4):1367–1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suh HS, Kim MO, Lee SC (2005) Inhibition of granulocyte-macrophage colony-stimulating factor signaling and microglial proliferation by anti-CD45RO: role of Hck tyrosine kinase and phosphatidylinositol 3-kinase/Akt. J Immunol 174(5):2712–2719

    Article  CAS  PubMed  Google Scholar 

  31. Vikman P, Beg S, Khurana TS, Hansen-Schwartz J, Edvinsson L (2006) Gene expression and molecular changes in cerebral arteries following subarachnoid hemorrhage in the rat. J Neurosurg 105(3):438–444

    Article  CAS  PubMed  Google Scholar 

  32. Witkowska AM, Borawska MH, Socha K, Kochanowicz J, Mariak Z, Konopka M (2009) TNF-α and sICAM-1 in intracranial aneurismal rupture. Arch Immunol Ther Exp (Warsz) 57(2):137–140

    Article  CAS  PubMed  Google Scholar 

  33. Woronicz JD, Calnan B, Ngo V, Winoto A (1994) Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367(6460):277–281

    Article  CAS  PubMed  Google Scholar 

  34. Wright HL, Chikura B, Bucknall RC, Moots RJ, Edwards SW (2011) Changes in expression of membrane TNF-α, NF-{κ}B activation and neutrophil apoptosis during active and resolved inflammation. Ann Rheum Dis 70(3):537–543

    Article  CAS  PubMed  Google Scholar 

  35. Yan SF, Fujita T, Lu J, Okada K, Shan Zou Y, Mackman N, Pinsky DJ, Stern DM (2000) Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nat Med 6:1355–1361

    Article  CAS  PubMed  Google Scholar 

  36. Yang CH, Fang IM, Lin CP, Yang CM, Chen MS (2005) Effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate on experimentally induced autoimmune anterior uveitis. Invest Ophthalmol Vis Sci 46(4):1339–1347

    Article  PubMed  Google Scholar 

  37. Zhou ML, Shi JX, Hang CH, Cheng HL, Qi XP, Mao L, Chen KF, Yin HX (2007) Potential contribution of nuclear factor-κB to cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. J Cereb Blood Flow Metab 27:1583–1592

    Article  CAS  PubMed  Google Scholar 

  38. Zhou Y, Martin RD, Zhang JH (2011) Advances in experimental subarachnoid hemorrhage. Acta Neurochir Suppl 110(Pt 1):15–21

    PubMed  Google Scholar 

  39. Zhuang Z, Zhou ML, You WC, Zhu L, Ma CY, Sun XJ, Shi JX (2012) Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neurosci 13(1):47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zong W-X, Lindsten T, Ross AJ, MacGregor GR, Thompson CB (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15:1481–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank S-C Wu, B.D., of the Neurosurgery Department at Kaohsiung Medical University, for her assistance in the all the experimental planning and supply of experimental material.

This work was supported by research grants from the Kaohsiung municipal Ta-Tung hospital of Taiwan (kmtth-99-026).

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chih-Zen Chang, Chih-Long Lin, Shiuh-Lin Hwang & Aij-Lie Kwan

  2. Department of Neurosurgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang, Shu-Chuan Wu, Chih-Long Lin, Shiuh-Lin Hwang & Aij-Lie Kwan

  3. Department of Neurosurgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

    Chih-Zen Chang

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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1007/s00701-024-05907-4"

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Chang, CZ., Wu, SC., Lin, CL. et al. RETRACTED ARTICLE: Purine anti-metabolite attenuates nuclear factor κB and related pro-inflammatory cytokines in experimental vasospasm. Acta Neurochir 154, 1877–1885 (2012). https://doi.org/10.1007/s00701-012-1452-8

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  • DOI: https://doi.org/10.1007/s00701-012-1452-8

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