Methylxanthines, inflammation, and cancer: fundamental mechanisms.

Methylxanthines are an integral part of everyday food and drink consumption even though the majority of humans do not identify them by their chemical name. The breakthrough in understanding the action(s) of methylxanthines was in large part due to the understanding that methylxanthines can function as antagonists of adenosine receptors. This represented an example of scientific search and was instructive in view of both new therapeutic options and alarming realizations. It was the subsequent demonstration of the in vivo critical role of A2A adenosine receptors in controlling excessive collateral inflammatory damage that attracted the attention of immunologists to the A2A-adenosine-receptor-antagonizing methylxanthines. We summarize here data showing that caffeine is capable of preventing the inhibition of antitumor T cells in a hypoxic tumor microenvironment. On the other hand, caffeine may exacerbate liver damage by weakening the tissue-protecting A2A adenosine receptor signaling during episodes of acute liver inflammation. However, methylxanthines may also prevent the excessive hepatic connective tissue deposition that is associated with the progression of chronic hepatitis to cirrhosis, which is one of the common causes of mortality.

[1]  V. Marks,et al.  PLASMA CAFFEINE CONCENTRATIONS IN OUTPATIENTS , 1982, The Lancet.

[2]  C. H. Jarboe,et al.  Effects of cimetidine on caffeine disposition in smokers and nonsmokers , 1982, Clinical pharmacology and therapeutics.

[3]  M. Sitkovsky,et al.  Cyclic AMP‐Dependent Protein Kinase as a Part of the Possible Down‐regulating Pathway in the Antigen Receptor‐Regulated Cytotoxic T Lymphocyte Conjugate Formation and Granule Exocytosis , 1988, Annals of the New York Academy of Sciences.

[4]  R. Vestal,et al.  Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst. , 1990, The Journal of allergy and clinical immunology.

[5]  B. Cronstein,et al.  The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. , 1990, The Journal of clinical investigation.

[6]  A. Klatsky,et al.  Alcohol, Smoking, Cofee, and Cirrhosis , 1992 .

[7]  A. Wendel,et al.  A T cell-dependent experimental liver injury in mice inducible by concanavalin A. , 1992, The Journal of clinical investigation.

[8]  G. Friedman,et al.  Coffee, tea, and mortality. , 1993, Annals of epidemiology.

[9]  A. G. Driver,et al.  Adenosine in bronchoalveolar lavage fluid in asthma. , 1993, The American review of respiratory disease.

[10]  Steve Huang,et al.  Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion , 1997 .

[11]  D. Rockey,et al.  Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  F. Chisari Cytotoxic T cells and viral hepatitis. , 1997, The Journal of clinical investigation.

[13]  Steve Huang,et al.  Memory of Extracellular Adenosine A2A Purinergic Receptor-mediated Signaling in Murine T Cells* , 1997, The Journal of Biological Chemistry.

[14]  S. Toyabe,et al.  Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice. , 1997, Journal of immunology.

[15]  Perturbation of the expression of the catalytic subunit C alpha of cyclic AMP-dependent protein kinase inhibits TCR-triggered secretion of IL-2 by T helper hybridoma cells. , 1997, Journal of immunology.

[16]  F. Chisari,et al.  Immune Pathogenesis of Hepatocellular Carcinoma , 1998, The Journal of experimental medicine.

[17]  K. Tanaka,et al.  Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. , 1998, International journal of epidemiology.

[18]  B. Fredholm,et al.  Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. , 1999, Pharmacological reviews.

[19]  S M Evans,et al.  Detection of hypoxia in human squamous cell carcinoma by EF5 binding. , 2000, Cancer research.

[20]  M. Taniguchi,et al.  Augmentation of Vα14 Nkt Cell–Mediated Cytotoxicity by Interleukin 4 in an Autocrine Mechanism Resulting in the Development of Concanavalin a–Induced Hepatitis , 2000, The Journal of experimental medicine.

[21]  G. Chrousos,et al.  Ligand-Activation of the Adenosine A2a Receptors Inhibits IL-12 Production by Human Monocytes , 2000, The Journal of Immunology.

[22]  A. Ohta,et al.  Indispensable Role for TNF-α and IFN-γ at the Effector Phase of Liver Injury Mediated by Th1 Cells Specific to Hepatitis B Virus Surface Antigen1 , 2000, The Journal of Immunology.

[23]  T. Papadopoulos,et al.  Importance of Kupffer cells for T-cell-dependent liver injury in mice. , 2000, The American journal of pathology.

[24]  A. Giaccia,et al.  Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  R. Guieu,et al.  High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock , 2000, Critical care medicine.

[26]  B. Rehermann Intrahepatic T Cells in Hepatitis B , 2000, The Journal of experimental medicine.

[27]  A. Ohta,et al.  Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage , 2001, Nature.

[28]  B. Fredholm,et al.  International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. , 2001, Pharmacological reviews.

[29]  M. Coleman,et al.  Coffee consumption and serum aminotransferases in middle-aged Japanese men. , 2001, Journal of clinical epidemiology.

[30]  M. Luster,et al.  The Role of Tumor Necrosis Factor-α in Liver Toxicity, Inflammation, and Fibrosis Induced by Carbon Tetrachloride , 2001 .

[31]  M. Luster,et al.  Role of inflammation in chemical-induced hepatotoxicity. , 2001, Toxicology letters.

[32]  A. Harris,et al.  Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. , 2001, Cancer research.

[33]  G. Corrao,et al.  Coffee, caffeine, and the risk of liver cirrhosis. , 2001, Annals of epidemiology.

[34]  Y. Noda,et al.  Suppressive Effect of Coffee on Lipopolysaccharide-induced Hepatitis in D-Galactosamine-sensitized Rats , 2001, Bioscience, biotechnology, and biochemistry.

[35]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[36]  P. Shepherd,et al.  Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. , 2002, The Journal of biological chemistry.

[37]  T. Lawrence,et al.  Anti-inflammatory lipid mediators and insights into the resolution of inflammation , 2002, Nature Reviews Immunology.

[38]  J. Fozard,et al.  Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat. , 2002, European journal of pharmacology.

[39]  Man-Fung Yuen,et al.  Viral hepatitis B , 2003, The Lancet.

[40]  A. Tverdal,et al.  Coffee intake and mortality from liver cirrhosis. , 2003, Annals of epidemiology.

[41]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[42]  J. Kaldor,et al.  Predicting progression to cirrhosis in chronic hepatitis C virus infection , 2003, Journal of viral hepatitis.

[43]  M. Yuen,et al.  Viral hepatitis C , 2003, The Lancet.

[44]  Acute liver failure in the United States , 2003 .

[45]  B. Cronstein,et al.  Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. , 2003, Arthritis and rheumatism.

[46]  S. Colgan,et al.  Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. , 2004, Blood.

[47]  Liping Huang,et al.  Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[48]  H. Yee,et al.  Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. , 2004, The American journal of pathology.

[49]  Francesco Donato,et al.  Hepatocellular carcinoma in cirrhosis: incidence and risk factors. , 2004, Gastroenterology.

[50]  S. Friedman,et al.  Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. , 2004, Gastroenterology.

[51]  William M. Lee Acetaminophen and the U.S. acute liver failure study group: Lowering the risks of hepatic failure , 2004, Hepatology.

[52]  Manfred Thiel,et al.  Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. , 2004, Annual review of immunology.

[53]  E. Casiglia,et al.  Unexpected effects of coffee consumption on liver enzymes , 1993, European Journal of Epidemiology.

[54]  J. Kelly,et al.  Caffeine suppresses TNF-α production via activation of the cyclic AMP/protein kinase A pathway , 2004 .

[55]  J. Everhart,et al.  Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. , 2005, Gastroenterology.

[56]  F. Kamali,et al.  Pharmacokinetic and pharmacodynamic responses to caffeine in poor and normal sleepers , 1995, Psychopharmacology.

[57]  C. Drake,et al.  Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. , 2005, Cancer cell.

[58]  A. Ohta,et al.  Oxygenation Inhibits the Physiological Tissue-Protecting Mechanism and Thereby Exacerbates Acute Inflammatory Lung Injury , 2005, PLoS biology.

[59]  J. Everhart,et al.  Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. , 2005, Gastroenterology.

[60]  A. Ohta,et al.  The 'danger' sensors that STOP the immune response: the A2 adenosine receptors? , 2005, Trends in immunology.

[61]  C. Moskaluk,et al.  Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. , 2005, Gastroenterology.

[62]  B. Cronstein,et al.  Adenosine A2A Receptor Stimulation Increases Angiogenesis by Down-Regulating Production of the Antiangiogenic Matrix Protein Thrombospondin 1 , 2005, Molecular Pharmacology.

[63]  Courtney M. Lappas,et al.  A2A Adenosine Receptor Induction Inhibits IFN-γ Production in Murine CD4+ T Cells1 , 2005, The Journal of Immunology.

[64]  A. Czaja Current concepts in autoimmune hepatitis. , 2005, Annals of hepatology.

[65]  C. Blank,et al.  Immune resistance orchestrated by the tumor microenvironment , 2006, Immunological reviews.

[66]  J. Kelly,et al.  Immunomodulatory effects of caffeine: friend or foe? , 2006, Pharmacology & therapeutics.

[67]  S. Friedman,et al.  Adenosine A2A receptors play a role in the pathogenesis of hepatic cirrhosis , 2006, British journal of pharmacology.

[68]  C. Ledent,et al.  Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis1 , 2006, The Journal of Immunology.

[69]  A. Ohta,et al.  A2A adenosine receptor protects tumors from antitumor T cells , 2006, Proceedings of the National Academy of Sciences.

[70]  Jonathan A. Rebhahn,et al.  T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5′-Adenosine Monophosphate to Adenosine1 , 2006, The Journal of Immunology.

[71]  Courtney M. Lappas,et al.  Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation , 2006, The Journal of experimental medicine.

[72]  S. Rosenberg,et al.  Adoptive immunotherapy for cancer: building on success , 2006, Nature Reviews Immunology.

[73]  V. Kuchroo,et al.  Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression , 2007, The Journal of experimental medicine.

[74]  B. Fredholm,et al.  1,3,7-Trimethylxanthine (Caffeine) May Exacerbate Acute Inflammatory Liver Injury by Weakening the Physiological Immunosuppressive Mechanism1 , 2007, The Journal of Immunology.

[75]  P. Vaupel,et al.  Hypoxia in cancer: significance and impact on clinical outcome , 2007, Cancer and Metastasis Reviews.

[76]  H. Eltzschig,et al.  HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. , 2008, Blood.

[77]  L. Chiriboga,et al.  Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine. , 2008, The American journal of pathology.

[78]  Jianzhu Chen,et al.  Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice , 2008, Proceedings of the National Academy of Sciences.

[79]  K. Ramalakshmi,et al.  A Perception on Health Benefits of Coffee , 2008, Critical reviews in food science and nutrition.

[80]  A. Ohta,et al.  Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia , 2008, Clinical Cancer Research.

[81]  D. Munn,et al.  Creating immune privilege: active local suppression that benefits friends, but protects foes , 2008, Nature Reviews Immunology.

[82]  Michael Dougan,et al.  Immune therapy for cancer. , 2009, Annual review of immunology.

[83]  A. Trautmann Extracellular ATP in the Immune System: More Than Just a “Danger Signal” , 2009, Science Signaling.

[84]  A. Douvdevani,et al.  Blocking adenosine A2A receptor reduces peritoneal fibrosis in two independent experimental models. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[85]  K. Oka,et al.  Protective effects of coffee‐derived compounds on lipopolysaccharide/d‐galactosamine induced acute liver injury in rats , 2009 .