Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

Abstract

Adenosine is an endogenous immunomodulator that has been shown to exhibit anti-inflammatory and immunosuppressive properties through a mechanism that is not fully established. Owing to the pivotal role of nuclear factor (NF)-κB in these responses, we tested the hypothesis that adenosine mediates its effects through suppression of NF-κB activation. We investigated the effects of adenosine on NF-κB activation induced by various inflammatory agents in human myeloid KBM-5 cells. The treatment of these cells with adenosine suppressed TNF-induced NF-κB activation, but had no effect on activation of another redox-sensitive transcription factor, AP-1. These effects were not restricted to myeloid cells, as NF-κB activation in other lymphocytic and epithelial cell types was also inhibited. The effect on TNF-induced NF-κB activation was selective as adenosine had minimal effect on NF-κB activation induced by H2O2, PMA, LPS, okadaic acid, or ceramide, suggesting differences in the pathway leading to NF-κB activation by different agents. Adenosine also suppressed NF-κB-dependent reporter gene expression activated by TNF or by overexpression of TNFR1, TRAF 2, NIK, and p65 subunit of NF-κB. The suppression of TNF-induced NF-κB activation by adenosine was found not to be because of inhibition of TNF-induced IκBα phosphorylation and degradation or IκBα kinase activation. The suppression of TNF-induced NF-κB activation was unique to adenosine, as neither its metabolites (inosine, AMP, and ATP) nor pyrimidines (thymidine and uridine) had any effect. Overall, our results clearly demonstrate that adenosine selectively suppresses TNF-induced NF-κB activation, which may contribute to its role in suppression of inflammation and of the immune system.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

TNFR1:

TNF receptor 1

PIS:

preimmune serum

IκB:

inhibitory subunit of NF-κB

SEAP:

secretory alkaline phosphatase

RA:

rheumatoid arthritis

PMA:

phorbol myristate acetate

LPS:

lipopolysaccharide

HIV:

human immunodeficiency virus

TRAF2:

TNF receptor-associated factor-2

TRADD:

TNF receptor-associated death domain

NIK:

NF-κB-inducing kinase

IKK:

IκBα kinase

IL-1:

interleukin-1

DMPX:

3,7-dimethyl-1-propargylxanthine

DPCPX:

8-cyclopentyl-1,3-dipropylxanthine

References

  • Albrecht H, Schook LB and Jongeneel CV . (1995). J. Inflamm., 45, 64–71.

  • Bergmann S, Shatrov V, Ratter F, Schiemann S, Schulze-Osthoff K and Lehmann V . (1994). J. Immunol., 153, 1736–1743.

  • Bonizzi G, Piette J, Merville MP and Bours V . (1997). J. Immunol., 159, 5264.

  • Bouma MG, van den Wildenberg FA and Buurman WA . (1997). Shock, 8, 313–320.

  • Bouma MG, Stad RK, van den Wildenberg FA and Buurman WA . (1994). J. Immunol., 153, 4159–4168.

  • Bouma MG, van den Wildenberg FA and Buurman WA . (1996). Am. J. Physiol., 270(2 Part 1), C522–C529.

  • Bowlin TL, Borcherding DR, Edwards III CK and McWhinney CD . (1997). Cell Mol. Biol. (Noisy-le-grand), 43, 345–349

  • Chaturvedi MM, Mukhopadhyay A and Aggarwal BB . (2000). Meth. Enzymol., 319, 585–601.

  • Cronstein BN . (1994). J. Appl. Physiol., 76, 5–13.

  • Darnay B, Ni J, Moore PA and Aggarwal BB . (1999). J. Biol. Chem., 274, 7724.

  • Daval JL, Nehlig A and Nicolas F . (1991). Life Sci., 49, 1435–1453.

  • Daval JL, Nicolas F and Doriat JF . (1996). Pharmacol. Ther., 71, 325–335.

  • de la Harpe J and Nathan CF . (1989). J. Immunol., 143, 596–602.

  • Ferrari D, Wesselborg S, Bauer MK and Schulze-Osthoff K . (1997). J. Cell Biol., 139, 1635–1643.

  • Finco TS, Beg AA and Baldwin AS . (1994). Proc. Natl. Acad. Sci. USA, 91, 11884.

  • Green PG, Basbaum AI, Helms C and Levine JD . (1991). Proc Natl Acad Sci USA, 88, 4162–4165.

  • Guo Y, Bolli R, Bao W, Wu WJ, Black Jr RG, Murphree SS, Salvatore CA, Jacobson MA and Auchampach JA . (2001). J. Mol. Cell Cardiol., 33, 825–830.

  • Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T and Cybulsky MI . (2000). Proc. Natl. Acad. Sci. USA, 97, 9052–9057.

  • Hasko G, Kuhel DG, Chen JF, Schwarzschild MA, Deitch EA, Mabley JG, Marton A and Szabo C . (2000a). FASEB J., 14, 2065–2074

  • Hasko G, Kuhel DG, Salzman AL and Szabo C . (2000b). Br. J. Pharmacol., 129, 909–914.

  • Hasko G, Szabo C, Nemeth ZH, Kvetan V, Pastores SM and Vizi ES . (1996). J. Immunol., 157, 4634–4640.

  • Janier MF, Vanoverschelde JL and Bergmann SR . (1993). Am. J. Physiol., 264(1 Part 2), H163–H170.

  • Jeong SY, Ahn SG, Lee JH, Kim HS, Kim JW, Rhim H, Jeong SW and Kim IK . (1999). J. Biol. Chem., 274, 18981–18988.

  • John GR, Simpson JE, Woodroofe MN, Lee SC and Brosnan CF . (2001). J. Neurosci., 21, 4134–4142.

  • Li C, Browder W and Kao RL . (1999) Am. J. Physiol., 276(2 Part 2), H543–H552

  • Li C, Ha T, Liu L, Browder W and Kao RL . (2000). Surgery, 127, 161–169.

  • Liu JS, John GR, Sikora A, Lee SC and Brosnan CF . (2000). J. Neurosci., 20, 5292–5299.

  • Li C, Kao RL, Ha T, Kelley J, Browder IW and Williams DL . (2001). Am. J. Physiol. Heart Circ. Physiol., 28, H1264–H1271.

  • Miagkov AV, Kovalenko DV, Brown CE, Didsbury JR, Cogswell JP, Stimpson SA, Baldwin AS and Makarov SS . (1998). Proc. Natl. Acad. Sci. USA, 95, 13 859–13 864.

  • Marangos PJ, von Lubitz D, Daval JL and Deckert J . (1990). Prog. Clin. Biol. Res., 361, 331–349.

  • McWhinney CD, Dudley MW, Bowlin TL, Peet NP, Schook L, Bradshaw M, De M, Borcherding DR and Edwards III CK . (1996). Eur. J. Pharmacol., 310, 209–216.

  • Mahon TM and O'Neill LA . (1995). J. Biol. Chem., 270, 28557.

  • Majumdar S and Aggarwal BB . (2001). J. Immunol., 167, 2911–2920.

  • Malinin NL, Boldin MP, Kovalenko AV and Wallach D . (1997). Nature, 385, 540.

  • Manna SK, Mukhopadhyay A and Aggarwal BB . (2000a). J. Immunol., 164, 4927–4934.

  • Manna SK, Sah NK and Aggarwal BB . (2000b). J. Biol. Chem., 275, 13297–13306.

  • Nasuhara Y, Adcock IM, Catley M, Barnes PJ and Newton R . (1999). J. Biol. Chem., 274, 19965.

  • Natarajan K, Singh S, Burke Jr TR, Grunberger D and Aggarwal BB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9090.

  • Nie Z, Mei Y, Ford M, Rybak L, Marcuzzi A, Ren H, Stiles GL and Ramkumar V . (1998). Mol Pharmacol., 53, 663–669.

  • Pahl HL . (1999). Oncogene, 18, 6853–6866.

  • Parmely MJ, Zhou WW, Edwards III CK, Borcherding DR, Silverstein R and Morrison DC . (1993). J. Immunol., 151, 389–396.

  • Reinstein LJ, Lichtman SN, Currin RT, Wang J, Thurman RG and Lemasters JJ . (1994). Hepatology, 19, 1445–1452.

  • Salvatore CA, Tilley SL, Latour AM, Fletcher DS, Koller BH and Jacobson MA . (2000). J. Biol. Chem., 275, 4429–4434.

  • Schrier DJ, Lesch ME, Wright CD and Gilbertsen RB . (1990). J. Immunol., 145, 1874–1879.

  • Sullivan GW, Linden J, Hewlett EL, Carper HT, Hylton JB and Mandell GL . (1990). J. Immunol., 145, 1537–1544.

  • Szabo C, Scott GS, Virag L, Egnaczyk G, Salzman AL, Shanley TP and Hasko G . (1998). Br. J. Pharmacol., 125, 379–387.

  • Traut TW . (1994). Mol. Cell Biochem., 140, 1–22.

  • Wagner DR, Combes A, McTiernan C, Sanders VJ, Lemster B and Feldman AM . (1998a). Cir. Res., 82, 47–56.

  • Wagner DR, McTiernan C, Sanders VJ and Feldman AM . (1998b). Circulation, 97, 521–524.

  • Xia D, Wang F and Parmely MJ . (2000). Biochem. Pharmacol., 60, 717–727.

  • Yin Y, Allen PD, Jia L and Kelsey SM . (2001). Leukemia Res., 25, 423–431.

  • Zwacka RM, Zhang Y, Zhou W, Halldorson J and Engelhardt JF . (1998). Hepatology, 28, 1022.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bharat B Aggarwal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Majumdar, S., Aggarwal, B. Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types. Oncogene 22, 1206–1218 (2003). https://doi.org/10.1038/sj.onc.1206184

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206184

Keywords

This article is cited by

Search

Quick links