Upregulation of Pro-inflammatory Cytokine Expression Following Chronic Paracetamol Treatment in Astrocyte

  • Nutnicha Tantarungsee
  • Waranurin Yisarakun
  • Thananya Thongtan
  • Laddawan Lalert
  • Sirinapa Srikam
  • Preecha Reuangwechvorachai
  • Praewphan Ingruanglert
  • Supang Maneesri-le Grand
ORIGINAL ARTICLE

Abstract

The present study aimed to investigate the effect of APAP treatment on the expression of pro-inflammatory cytokines in the astrocytes. The mouse astrocyte cells (C8-D1A) were treated with APAP at the concentration of 100 μM for 24 h, 16 and 28 days. The expressions of pro-inflammatory cytokines and NF-kB were determined using western blot analysis. Furthermore, the expression and localization of phosphorylation of NF-kB were detected by immunohistochemical and immunofluorescent analysis. The ultrastructure of C8-D1A cells was as well monitored. The results revealed that acute APAP treatment (24 h) had no effect on the expression of pro-inflammatory cytokines and pNF-kB. This treatment did not alter the ultrastructure of C8-D1A cells when compared with those in the control cells. However, the results obtained from the study on chronic APAP-treated cells (16 and 28 days) showed the different effect of APAP treatment. The results obtained from western blot analysis showed the increment of pro-inflammatory cytokine (IL-1β and TNF-α) expressions and the activation of NF-kB signaling pathway. Nuclear translocation of pNF-kB and alteration of several cell structures were well observed in the C8-D1A cells with chronic APAP treatment. The results obtained from this study suggest that chronic APAP treatment can induce an upregulation of pro-inflammatory cytokines (IL-1β and TNFα) in astrocytes. This alteration implies the involvement of the activation of NF-kB signaling pathway.

Keywords

Paracetamol Astrocyte Pro-inflammatory cytokines NF-kB signaling Ultrastructure 

Notes

Acknowledgments

This study was supported by the National Research Council of Thailand (NRCT, GB_B_60_071_30_15 and GB_B_60_074_30_18)

References

  1. Anderson BJ (2008) Paracetamol (acetaminophen): mechanisms of action. Paediatr Anaesth 18(10):915–921.  https://doi.org/10.1111/j.1460-9592.2008.02764.x CrossRefPubMedGoogle Scholar
  2. Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336(15):1066–1071.  https://doi.org/10.1056/nejm199704103361506 CrossRefPubMedGoogle Scholar
  3. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006) Paracetamol: new vistas of an old drug. CNS Drug Rev 12(3-4):250–275.  https://doi.org/10.1111/j.1527-3458.2006.00250.x CrossRefPubMedGoogle Scholar
  4. Chantong C, Yisarakun W, Thongtan T, Maneesri-le Grand S (2013) Increase of pro-inflammatory cytokine expression in hippocampus following chronic paracetamol treatment in rats. Asian Arch Pathol 9:137–146Google Scholar
  5. Combes V, Guillemin GJ, Chan-Ling T, Hunt NH, Grau GE (2012) The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes. Trends Parasitol 28(8):311–319.  https://doi.org/10.1016/j.pt.2012.05.008 CrossRefPubMedGoogle Scholar
  6. Dambach DM, Durham SK, Laskin JD, Laskin DL (2006) Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol 211(2):157–165.  https://doi.org/10.1016/j.taap.2005.06.024 CrossRefPubMedGoogle Scholar
  7. Dimova S, Hoet PH, Nemery B (2000) Paracetamol (acetaminophen) cytotoxicity in rat type II pneumocytes and alveolar macrophages in vitro. Biochem Pharmacol 59(11):1467–1475.  https://doi.org/10.1016/S0006-2952(00)00257-4 CrossRefPubMedGoogle Scholar
  8. Fakunle PB, AJA EBO, Alamu OA, Daramola AK (2011) Neurohistological degeneration of the hippocampal formation following chronic simultaneous administration of ethanol and acetaminophen in adult wistar rats (Rattus norvegicus). J Pharmacol Toxicol 6(8):701–709.  https://doi.org/10.3923/jpt.2011.701.709 CrossRefGoogle Scholar
  9. He Y, Yao Y, Tsirka SE, Cao Y (2014) Cell-culture models of the blood–brain barrier. Stroke 45(8):2514–2526.  https://doi.org/10.1161/strokeaha.114.005427 CrossRefPubMedPubMedCentralGoogle Scholar
  10. van Kralingen C, Kho DT, Costa J, Angel CE, Graham ES (2013) Exposure to inflammatory cytokines IL-1β and TNFα induces compromise and death of astrocytes; implications for chronic neuroinflammation. PLoS One 8(12):e84269.  https://doi.org/10.1371/journal.pone.0084269 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Lawrence T (2009) The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6).  https://doi.org/10.1101/cshperspect.a001651
  12. Moynagh PN (2005) The interleukin-1 signalling pathway in astrocytes: a key contributor to inflammation in the brain. J Anat 207(3):265–269.  https://doi.org/10.1111/j.1469-7580.2005.00445.x CrossRefPubMedPubMedCentralGoogle Scholar
  13. Nedergaard M, Verkhratsky A (2012) Artifact versus reality—how astrocytes contribute to synaptic events. Glia 60(7):1013–1023.  https://doi.org/10.1002/glia.22288 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Pacifici GM, Allegaert K (2015) Clinical pharmacology of paracetamol in neonates: a review. Curr Ther Res,Clin Exp 77:24–30.  https://doi.org/10.1016/j.curtheres.2014.12.001 CrossRefGoogle Scholar
  15. Posadas I, Santos P, Blanco A, Munoz-Fernandez M, Cena V (2010) Acetaminophen induces apoptosis in rat cortical neurons. PLoS One 5(12):e15360.  https://doi.org/10.1371/journal.pone.0015360 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Posadas I, Santos P, Cena V (2012) Acetaminophen induces human neuroblastoma cell death through NFKB activation. PLoS One 7(11):e50160.  https://doi.org/10.1371/journal.pone.0050160 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol (Clifton, NJ) 814:3–7.  https://doi.org/10.1007/978-1-61779-452-0_1 CrossRefGoogle Scholar
  18. Shih RH, Wang CY, Yang CM (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8.  https://doi.org/10.3389/fnmol.2015.00077
  19. Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist Rev J Bringing Neurobiol, Neurol Psychiatry 20(2):160–172.  https://doi.org/10.1177/1073858413504466 Google Scholar
  20. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35.  https://doi.org/10.1007/s00401-009-0619-8 CrossRefPubMedGoogle Scholar
  21. Sudano I, Flammer AJ, Periat D, Enseleit F, Hermann M, Wolfrum M, Hirt A, Kaiser P, Hurlimann D, Neidhart M, Gay S, Holzmeister J, Nussberger J, Mocharla P, Landmesser U, Haile SR, Corti R, Vanhoutte PM, Luscher TF, Noll G, Ruschitzka F (2010) Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation 122(18):1789–1796.  https://doi.org/10.1161/circulationaha.110.956490 CrossRefPubMedGoogle Scholar
  22. Tak PP, Firestein GS (2001) NF-κB: a key role in inflammatory diseases. J Clin Investig 107(1):7–11.  https://doi.org/10.1172/JCI11830 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Tripathy D, Grammas P (2009a) Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress. J Neuroinflammation 6(1):10.  https://doi.org/10.1186/1742-2094-6-10 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Tripathy D, Grammas P (2009b) Acetaminophen protects brain endothelial cells against oxidative stress. Microvasc Res 77(3):289–296.  https://doi.org/10.1016/j.mvr.2009.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Wongprom B, Maneesri-le Grand S, Thongtan T (2015) Long-term paracetamol treatment induces interleukin-1β expression in human microglial cells. Chula Med J 59(3):253–263Google Scholar
  26. Yisarakun W, Supornsilpchai W, Chantong C, Srikiatkhachorn A, Maneesri-le Grand S (2014) Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model. Microvasc Res 94:36–46.  https://doi.org/10.1016/j.mvr.2014.04.012 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Nutnicha Tantarungsee
    • 1
  • Waranurin Yisarakun
    • 2
  • Thananya Thongtan
    • 3
  • Laddawan Lalert
    • 1
  • Sirinapa Srikam
    • 1
  • Preecha Reuangwechvorachai
    • 1
  • Praewphan Ingruanglert
    • 4
  • Supang Maneesri-le Grand
    • 1
  1. 1.Department of Pathology, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  2. 2.Department of Biomedical Sciences, Faculty of Allied Health SciencesBurapha UniversityChonBuriThailand
  3. 3.Department of Biochemistry, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  4. 4.Stem Cells and Cell Therapy Research Unit, Faculty of MedicineChulalongkorn UniversityBangkokThailand

Personalised recommendations