Is There a Relation between Adenosine and Caffeines’ Mechanisms of Action and Toll-Like Receptor-4 (TLR-4)?


Previous studies showed that endogenous adenosine, an anti-inflammatory agent, was released at sites of injury and inflammation thereby decreasing the excessive production of pro-inflammatory cytokines. Caffeine, a non-specific adenosine blocker, has been reported in several studies to have opposing immune-modulatory effects. In this study, the effects of caffeine and adenosine on TLR-4 in promoting or decreasing the production of TNF-α and IL-12 by LPS-stimulated monocytes were investigated. Monocytes were isolated using Pluribead® kit from pooled blood obtained from ten volunteers. The monocytes were then incubated for 24 hours with Lipopolysaccharide (pLPS) extracted from Escherichia coli (aTLR-4 ligand activator), adenosine, caffeine and LPS extracted from Rhodobacter sphaeroides (LPS-RS, a TLR-4 ligand blocker), each alone or in different combinations. Later, the levels of pro-inflammatory cytokines TNFα and IL-12 were assessed in supernatants using an Enzyme Linked Immuno Assay (ELISA). Caffeine and adenosine significantly reduced the amount of TNFα and IL-12 produced by LPS-stimulated monocytes. Regarding non-stimulated and LPS-RS blocked monocytes, the presence of adenosine and caffeine significantly decreased TNFα levels produced by these cells but had little or non-significant effect on the levels of IL-12. In conclusion, both caffeine and adenosine blocked the production of the pro-inflammatory cytokines by pLPS-stimulated-monocytes. TLR-4 did not appear to be involved in the signaling pathway of caffeine and adenosine since blocking of TLR-4 did not abolish the effects of adenosine and caffeine on production of cytokines, in particular TNF-α.

Share and Cite:

Moodad, S. , Al-Akl, N. , Simaan, J. and Abdelnoor, A. (2015) Is There a Relation between Adenosine and Caffeines’ Mechanisms of Action and Toll-Like Receptor-4 (TLR-4)?. Open Journal of Immunology, 5, 215-221. doi: 10.4236/oji.2015.54017.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Alexander, C. and Rietschel, E.T. (2001) Invited Review: Bacterial Lipopolysaccharides and Innate Immunity. Journal of Endotoxin Research, 7, 167-202.
[2] Fujihara, M., Muroi, M., Tanamoto, K.I., Suzuki, T., Azuma, H. and Ikeda, H. (2003) Molecular Mechanisms of Macrophage Activation and Deactivation by Lipopolysaccharide: Roles of the Receptor Complex. Pharmacology & Therapeutics, 100, 171-194.
[3] Park, B.S. and Lee, J.O. (2013) Recognition of Lipopolysaccharide Pattern by TLR4 Complexes. Experimental & Molecular Medicine, 45, e66.
[4] Bryant, C.E., Spring, D.R., Gangloff, M. and Gay, N.J. (2010) The Molecular Basis of the Host Response to Lipopolysaccharide. Nature Reviews Microbiology, 8, 8-14.
[5] Liaunardy-Jopeace, A. and Gay, N.J. (2014) Molecular and Cellular Regulation of Toll-Like Receptor-4 Activity Induced by Lipopolysaccharide Ligands. Frontiers in Immunology, 5, 473.
[6] Teghanemt, A., Zhang, D., Levis, E.N., Weiss, J.P. and Gioannini, T.L. (2005) Molecular Basis of Reduced Potency of Underacylated Endotoxins. The Journal of Immunology, 175, 4669-4676.
[7] Coats, S.R., Pham, T.T.T., Bainbridge, B.W., Reife, R.A. and Darveau, R.P. (2005) MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to Antagonize Escherichia coli Lipopolysaccharide at the TLR4 Signaling Complex. The Journal of Immunology, 175, 4490-4498.
[8] Haskó, G. and Cronstein, B.N. (2004) Adenosine: An Endogenous Regulator of Innate Immunity. Trends in Immunology, 25, 33-39.
[9] Haskó, G., Linden, J., Cronstein, B. and Pacher, P. (2008) Adenosine Receptors: Therapeutic Aspects for Inflammatory and Immune Diseases. Nature Reviews Drug Discovery, 7, 759-770.
[10] McNeill, B.W. (2004) Adenosine Receptor Mediated Inhibition of Tumor Necrosis Factor Alpha in Human Monocytic Cells. Doctoral Dissertation, University of Georgia.
[11] McColl, S.R., St-Onge, M., Dussault, A.A., Laflamme, C., Bouchard, L., Boulanger, J. and Pouliot, M. (2006) Immunomodulatory Impact of the A2A Adenosine Receptor on the Profile of Chemokines Produced by Neutrophils. The FASEB Journal, 20, 187-189.
[12] Hamano, R., Takahashi, H.K., Iwagaki, H., Kanke, T., Liu, K., Yoshino, T. and Tanaka, N. (2008) Stimulation of Adenosine A2A Receptor Inhibits LPS-Induced Expression of Intercellular Adhesion Molecule 1 and Production of TNF-α in Human Peripheral Blood Mononuclear Cells. Shock, 29, 154-159.
[13] Horrigan, L.A., Kelly, J.P. and Connor, T.J. (2006) Immunomodulatory Effects of Caffeine: Friend or Foe? Pharmacology & Therapeutics, 111, 877-892.
[14] Horrigan, L.A., Kelly, J.P. and Connor, T.J. (2004) Caffeine Suppresses TNF-α Production via Activation of the Cyclic AMP/Protein Kinase A Pathway. International Immunopharmacology, 4, 1409-1417.
[15] Deree, J., Martins, J.O., Melbostad, H., Loomis, W.H. and Coimbra, R. (2008) Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition. Clinics, 63, 321- 328.
[16] Ramakers, B.P., Riksen, N.P., van den Broek, P., Franke, B., Peters, W.H., van der Hoeven, J.G. and Pickkers, P. (2011) Circulating Adenosine Increases during Human Experimental Endotoxemia but Blockade of Its Receptor Does Not Influence the Immune Response and Subsequent Organ Injury. Critical Care, 15, R3.
[17] Ohta, A., Lukashev, D., Jackson, E.K., Fredholm, B.B. and Sitkovsky, M. (2007) 1, 3, 7-Trimethylxanthine (Caffeine) May Exacerbate Acute Inflammatory Liver Injury by Weakening the Physiological Immunosuppressive Mechanism. The Journal of Immunology, 179, 7431-7438.
[18] Meiners, I., Hauschildt, S., Nieber, K. and Münch, G. (2004) Pentoxyphylline and Propentophylline Are Inhibitors of TNF-α Release in Monocytes Activated by Advanced Glycation Endproducts. Journal of Neural Transmission, 111, 441-444.
[19] Varani, K., Portaluppi, F., Gessi, S., Merighi, S., Vincenzi, F., Cattabriga, E. and Borea, P.A. (2005) Caffeine Intake Induces an Alteration in Human Neutrophil A2A Adenosine Receptors. Cellular and Molecular Life Sciences CMLS, 62, 2350-2358.
[20] Aste-Amezaga, M., Ma, X., Sartori, A. and Trinchieri, G. (1998) Molecular Mechanisms of the Induction of IL-12 and Its Inhibition by IL-10. The Journal of Immunology, 160, 5936-5944.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.