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The mechanisms of methotrexate’s action in the treatment of inflammatory disease

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Methotrexate

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

The introduction of methotrexate for the therapy of rheumatoid arthritis and other forms of inflammatory arthritis has revolutionized the way in which these diseases are now treated. Because methotrexate was introduced empirically for the treatment of inflammatory disease without any specific understanding of a biological basis for its antiinflammatory properties, no improvements on this line of therapy have yet been introduced. A number of recent studies suggest several potential mechanisms of action and new agents developed on the basis of these mechanisms are currently being studied. We will discuss here the biochemical mechanisms by which methotrexate may suppress the inflammation of rheumatoid arthritis.

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References

  1. Hershfield MS, Kredich NM, Ownby DR, Ownby H, Buckley R (1979) In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2’-deoxyadenosine in adenosine deaminase-deficient patients. J Clin Invest 63: 807–811

    Article  PubMed  CAS  Google Scholar 

  2. Kredich NM, Hershfield MS (1979) S-Adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci (USA) 76: 2450–2455

    Article  CAS  Google Scholar 

  3. Hershfield MS, Kurtzberg J, Aiyar VN, Suh EJ, Schiff R (1985) Abnormalities in S-adenosylhomocysteine hydrolysis, ATP catabolism, and lymphoid differentiation in adenosine deaminase deficiency. Ann NY Acad Sci 451: 78–86

    Article  PubMed  CAS  Google Scholar 

  4. Hershfield MS, Krodich NM (1978) S-adenosylhomocysteine hydrolase is an adenosine-binding protein: a target for adenosine toxicity. Science 202: 757–760

    Article  PubMed  CAS  Google Scholar 

  5. Jurgensen CH, Wolberg G, Zimmerman TP (1989) Inhibition of neutrophil adherence to endothelial cells by 3- deazaadenosine. Agents Actions 27: 398–400

    Article  PubMed  CAS  Google Scholar 

  6. Jurgensen CH, Huber BE, Zimmerman TP, Wolberg G (1990) 3-deazaadenosine inhibits leukocyte adhesion and ICAM-1 biosynthesis in tumor necrosis factor-stimulated human endothelial cells. J Immunol 144: 653–661

    PubMed  CAS  Google Scholar 

  7. Prus KL, Wolberg G, Keller PM, Fyfe JA, Stopford CR, Zimmerman TP (1989) 3deazaadenosine 5’-triphosphate: a novel metabolite of 3- deazaadenosine in mouse leukocytes. Bio Pharmacol 38: 509–517

    Article  CAS  Google Scholar 

  8. Stopford CR, Wolberg G, Prus KL, Reynolds-Vaughn R, Zimmerman TP (1985) 3-deazaadenosine-induced disorganization of macrophage microfilaments. Proc Natl Acad Sci (USA) 82: 4060–4064

    Article  CAS  Google Scholar 

  9. Zimmerman TP, Wolberg G, Duncan GS (1978) Inhibition of lymphocyte-mediated cytolysis by 3-deazaadenosine: evidence for a methylation reaction essential for cytolysis. Proc Natl Acad Sci (USA) 75: 6220–6224

    Article  CAS  Google Scholar 

  10. Smith DM, Johnson JA, Turner RA (1991) Biochemical perturbations of BW 91Y (3deazaadenosine) on human neutrophil chemotactic potential and lipid metabolism. Int J Tiss React 13: 1–18

    CAS  Google Scholar 

  11. Flescher E, Bowlin TL, Ballester A, Houk R, Talal N (1989) Increased polyamines may downregulate interleukin 2 production in rheumatoid arthritis. J Clin Invest 83: 1356–1362

    Article  PubMed  CAS  Google Scholar 

  12. Flescher E, Bowlin TL, Talal N (1992) Regulation of IL-2 production by mononuclear cells from rheumatoid arthritis synovial fluids. Clin Exp Imm 87: 435–437

    Article  CAS  Google Scholar 

  13. Nesher G, Moore TL (1990) The in vitro effects of methotrexate on peripheral blood mononuclear cells. Modulation by methyl donors and spermidine. Arthritis Rheum 33: 954–959

    Article  PubMed  CAS  Google Scholar 

  14. Yukioka K, Wakitani S, Yukioka M, Furumitsu Y, Shichikawa K, Ochi T, Goto H, MatsuiYuasa I, Otani S, Nishizawa Y, et al (1992) Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis. J Rheum 19: 689–692

    PubMed  CAS  Google Scholar 

  15. Talal N, Tovar Z, Dauphinee MJ, Flescher E, Dang H, Galarza D (1988) Abnormalities of T cell activation in the rheumatoid synovium detected with monoclonal antibodies to CD3. Scand J Rheum — Supplement 76: 175–182

    Article  CAS  Google Scholar 

  16. Allegra CJ, Drake JC, Jolivet J, Chabner BA (1985) Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid poly-glutamates. Proc Natl Acad Sci (USA) 82: 4881–4885

    Article  CAS  Google Scholar 

  17. Chabner BA, Allegra CJ, Curt GA, Clendeninn NJ, Baram J, Koizumi S, Drake JC, Jolivet J (1985) Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest 76: 907–912

    Article  PubMed  CAS  Google Scholar 

  18. Baggott JE, Morgan SL, Koopman WJ (1998) The effect of methotrexate and 7-hydroxymethotrexate on rat adjuvant arthritis and on urinary aminoimidazole carboxamide excretion. Arthritis Rheum 41: 1407–1410

    Article  PubMed  CAS  Google Scholar 

  19. Luhby AL, Cooperman JH (1962) Aminoimidazole carboxamide excretion in vitamin B 12 and folic acid deficiencies. Lancet 2: 1381–1382

    Article  PubMed  CAS  Google Scholar 

  20. Cronstein BN, Naime D, Ostad E (1993) The antiinflammatory mechanism of methotrexate: increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 92: 2675–2682

    Article  PubMed  CAS  Google Scholar 

  21. Gruber HE, Hoffer ME, McAllister DR, Laikind PK, Lane TA, Schmid-Schoenbein GW, Engler RL (1989) Increased adenosine concentration in blood from ischemic myocardium by AICA riboside: effects on flow, granulocytes and injury. Circulation 80: 1400–1411

    Article  PubMed  CAS  Google Scholar 

  22. Morabito L, Montesinos MC, Schreibman DM, Balter L, Thompson LF, Resta R, Carlin G, Huie MA, Cronstein BN (1998) Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5’-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 101: 295–300

    Article  PubMed  CAS  Google Scholar 

  23. Montesinos MC, Yap IS, Desai A, Posadas I, McCrary CT, Cronstein BN (2000) Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonist theophylline and caffeine. Arthritis Rheum 43: 656–663

    Article  PubMed  CAS  Google Scholar 

  24. Baggott JE, Vaughn WH, Hudson BB (1986) Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5’-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J 236: 193–200

    PubMed  CAS  Google Scholar 

  25. Poulsen SA, Quinn RJ (1998) Adenosine receptors: new opportunities for future drugs. Bioorg Med Chem 6: 619–641

    Article  PubMed  CAS  Google Scholar 

  26. Salmon JE, Brogle N, Brownlie C, Edberg JC, Chen B-X, Erlanger BF (1993) Human mononuclear phagocytes express adenosine Al receptors: a novel mechanism for differential regulation of Fc-gamma receptor function. Jlmmunol 151: 2775–2785

    CAS  Google Scholar 

  27. Elliott KRF, Stevenson HC, Miller PJ, Leonard EJ (1986) Synergistic action of adenosine and Fmet-leu-phe in raising cyclic AMP content of purified human monocytes. Biochem Biophys Res Comm 138: 1376–1382

    Article  CAS  Google Scholar 

  28. Leonard EJ, Shenai A, Skeel A (1987) Dynamics of chemotactic peptide-induced superoxide generation by human monocytes. Inflammation 11: 229–240

    Article  PubMed  CAS  Google Scholar 

  29. Hasko G, Szabo C, Nemeth ZH, Kvetan V, Pastores SM, Vizi ES (1996) Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. Jlmmunol 157: 4634–4640

    CAS  Google Scholar 

  30. Hon WM, Moochhala S, Khoo HE (1997) Adenosine and its receptor agonists potentiate nitric oxide synthase expression induced by lipopolysaccharide in RAW 264.7 murine macrophages. Life Sciences 60: 1327–1335

    Article  PubMed  CAS  Google Scholar 

  31. Lappin D, Whaley K (1984) Adenosine A2 receptors on human monocytes modulate C2 production. Clin Exp Immunol 57: 454–460

    PubMed  CAS  Google Scholar 

  32. Merrill JT, Coffey D, Shen C, Zakharenko 0, Zhang HW, Lahita RG, Cronstein BN (1995) Mechanisms of rheumatoid nodulosis: methotrexate-enhanced monocyte fusion requires protein synthesis and intact microtubules. Arth Rheum 38 (Suppl): S157

    Article  Google Scholar 

  33. Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R (1983) Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. JExp Med 158: 1160–1177

    Article  CAS  Google Scholar 

  34. Cronstein BN, Duguma L, Nicholls D, Hutchison A, Williams M (1990) The adenosine/neutrophil paradox resolved. Human neutrophils possess both Al and A2 receptors which promote chemotaxis and inhibit 02-generation, respectively. J Clin Invest 85: 1150–1157

    Article  PubMed  CAS  Google Scholar 

  35. van Calker D, Steber R, Klotz KN, Greil W (1991) Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses. Eur J Pharmacol 206: 285–290

    Article  PubMed  Google Scholar 

  36. Fredholm BB, Zhang Y, van der Ploeg I (1996) Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. Naunyn-Schmiedebergs Archiv Pharmacol 354: 262–267

    CAS  Google Scholar 

  37. Marone G, Thomas L, Lichtenstein L (1980) The role of agonists that activate adenylate cyclase in the control of cAMP metabolism and enzyme release by human polymorphonuclear leukocytes. Jlmmunol 125: 2277–2283

    CAS  Google Scholar 

  38. McGarrity ST, Stephenson AH, Webster RO (1989) Regulation of human neutrophil functions by adenine nucleotides. Jlmmunol 142: 1986–1994

    Google Scholar 

  39. Cronstein BN, Kramer SB, Rosenstein ED, Korchak HM, Weissmann G, Hirschhorn R (1988) Occupancy of adenosine receptors raises cyclic AMP alone and in synergy with occupancy of chemoattractant receptors and inhibits membrane depolarization. Biochem J 252: 709–715

    PubMed  CAS  Google Scholar 

  40. Bouma MG, Jeunhomme TMMA, Boyle DL, Dentener MA, Voitenok NN, van den Wildenberg FAJM, Buurman WA (1997) Adenosine inhibits neutrophil degranulation in activated human whole blood; involvement of adenosine A2 and A3 receptors. J Immunol 158: 5400–5408

    PubMed  CAS  Google Scholar 

  41. Richter J (1992) Effect of adenosine analogues and cAMP-raising agents on TNF-, GMCSF-, and chemotactic peptide-induced degranulation in single adherent neutrophils. J Leukocyte Biol 51: 270–275

    CAS  Google Scholar 

  42. Schmeichel CJ, Thomas LL (1987) Methylxanthine bronchodilators potentiate multiple human neutrophil functions. J Immunol 138: 1896–1903

    PubMed  CAS  Google Scholar 

  43. Rose FR, Hirschhorn R, Weissmann G, Cronstein BN (1988) Adenosine promotes neutrophil chemotaxis. JExp Med 167: 1186–1194

    Article  CAS  Google Scholar 

  44. Salmon JE, Cronstein BN (1990) Fcgamma Receptor-Mediated functions in neutrophils are modulated by adenosine receptor occupancy: Al receptors are stimulatory and A2 receptors are inhibitory. J Immunol 145: 2235–2240

    PubMed  CAS  Google Scholar 

  45. Cronstein BN, Levin RI, Philips MR, Hirschhorn R, Abramson SB, Weissmann G (1992) Neutrophil adherence to endothelium is enhanced via adenosine Al receptors and inhibited via adenosine A2 receptors. Jlmmunol 148: 2201–2206

    CAS  Google Scholar 

  46. Zalavary S, Stendahl O, Bengtsson T (1994) The role of cyclic AMP, calcium and filamentous actin in adenosine modulation of Fc receptor-mediated phagocytosis in human neutrophils. Biochim Biophys Acta 1222: 249–256

    Article  PubMed  CAS  Google Scholar 

  47. Firestein GS, Bullough DA, Erion MD, Jimenez R, Ramirez-Weinhouse M, Barankiewicz J, Smith CW, Gruber HE, Mullane KM (1995) Inhibition of neutrophil adhesion by adenosine and an adenosine kinase inhibitor: the role of selectins. J Immunol 154: 326–334

    PubMed  CAS  Google Scholar 

  48. Wollner A, Wollner S, Smith JB (1993) Acting via A2 receptors, adenosine inhibits the upregulation of Mac-1 (CD11b/CD18) expression on FMLP-stimulated neutrophils. Am J Resp Cell Mol Biol 9: 179–185

    CAS  Google Scholar 

  49. Thiel M, Chambers JD, Chouker A, Fischer S, Zourelidis C, Bardenheuer HJ, Arfors KE, Peter K (1996) Effect of adenosine on the expression of beta(2) integrins and L-selectin of human polymorphonuclear leukocytes in vitro. J Leuko Biol 59: 671–682

    CAS  Google Scholar 

  50. Cronstein BN, Levin RI, Belanoff J, Weissmann G, Hirschhorn R (1986) Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells. J Clin Invest 78: 760–770

    Article  PubMed  CAS  Google Scholar 

  51. Boisseau MR, Pruvost A, Renard M, Closse C, Belloc F, Seigneur M, Maurel A (1996) Effect of buflomedil on the neutrophil-endothelial cell interaction under inflammatory and hypoxia conditions. Haemostasis 26: 182–188

    PubMed  CAS  Google Scholar 

  52. Zhao ZQ, Sato H, Williams MW, Fernandez AZ, Vinten-Johansen J (1996) Adenosine A2-receptor activation inhibits neutrophil-mediated injury to coronary endothelium. Amer J Physiol 271: H1456–1464

    PubMed  CAS  Google Scholar 

  53. Minamino T, Kitakaze M, Node K, Funaya H, Inoue M, Hori M, Kamada T (1996) Adenosine inhibits leukocyte-induced vasoconstriction. Amer J Physiol 271: H2622–2628

    PubMed  CAS  Google Scholar 

  54. Jordan JE, Zhao ZQ, Sato H, Taft S, Vinten-Johansen J (1997) Adenosine A2 receptor activation attenuates reperfusion injury by inhibiting neutrophil accumulation, superoxide generation and coronary endothelial adherence. J Pharmacol Exp Therapeutics 280: 301–309

    CAS  Google Scholar 

  55. Walker BA, Rocchini C, Boone RH, Ip S, Jacobson MA (1997) Adenosine A2a receptor activation delays apoptosis in human neutrophils. Jlmmunol 158: 2926–2931

    CAS  Google Scholar 

  56. Feoktistov I, Biaggioni I (1995) Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest 96: 1979–1986

    Article  PubMed  CAS  Google Scholar 

  57. Hannon JP, Pfannkuche HJ, Fozard JR (1995) A role for mast cells in adenosine A3 receptor-mediated hypotension in the rat. Br J Pharmacol 115: 945–952

    Article  PubMed  CAS  Google Scholar 

  58. Ali H, Choi OH, Fraundorfer PF, Yamada K, Gonzaga HM, Beaven MA (1996) Sustained activation of phospholipase D via adenosine A3 receptors is associated with enhancement of antigen-and Ca(2+)-ionophore-induced secretion in a rat mast cell line. J Pharmacol Exp Therapeutics 276: 837–845

    CAS  Google Scholar 

  59. Fozard JR, Pfannkuche HJ, Schuurman HJ (1996) Mast cell degranulation following adenosine A3 receptor activation in rats. Eur J Pharmacol 298: 293–297

    Article  PubMed  CAS  Google Scholar 

  60. Shepherd RK, Linden J, Duling BR (1996) Adenosine-induced vasoconstriction in vivo Role of the mast cell and A3 adenosine receptor. Circ Res 78: 627–634

    Article  PubMed  CAS  Google Scholar 

  61. Meade CJ, Mierau J, Leon I, Ensinger HA (1996) In vivo role of the adenosine A3 receptor: N6–2-(4-aminophenyl)ethyladenosine induces bronchospasm in BDE rats by a neurally mediated mechanism involving cells resembling mast cells. J Pharmacol Exp Therapeutics 279: 1148–1156

    CAS  Google Scholar 

  62. Firestein GS, Paine MM, Boyle DL (1994) Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arth Rheum 37: 193–200

    Article  CAS  Google Scholar 

  63. Boyle DL, Sajjadi FG, Firestein GS (1996) Inhibition of synoviocyte collagenase gene expression by adenosine receptor stimulation. Arth Rheum 39: 923–930

    Article  CAS  Google Scholar 

  64. Sexl V, Mancusi G, Baumgartner-Parzer S, Schutz W, Freissmuth M (1995) Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors. Br J Pharmacol 114: 1577–1586

    Article  PubMed  CAS  Google Scholar 

  65. Ethier MF, Chander V, Dobson JG Jr (1993) Adenosine stimulates proliferation of human endothelial cells in culture. Amer J Physiol 265: H131–H138

    PubMed  CAS  Google Scholar 

  66. Bouma MG, van den Wildenberg FAJM, Buurman WA (1996) Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. Amer J Physiol 39: C522–0529

    Google Scholar 

  67. Li J, Fenton RA, Wheeler HB, Powell CC, Peyton BD, Cutler BS, Dobson JG, Jr (1998) Adenosine A2a receptors increase arterial endothelial cell nitric oxide. J Surg Res 80: 357–364

    Article  PubMed  CAS  Google Scholar 

  68. Singh Y, Sharma M, Singh RR, Kumar A, Malaviya R, Malaviya AN (1992) Methotrexate: clinical and immunological effects in refractory rheumatoid arthritis. J Assoc Physicians India 40: 658–661

    PubMed  CAS  Google Scholar 

  69. Drosos AA, Psychos D, Andonopoulos AP, Stefanaki-Nikou S, Tsianos EB, Moutsopoulos HM (1990) Methotrexate therapy in rheumatoid arthritis. A two year prospective follow-up. Clin Rheumatol 9: 333–341

    Article  PubMed  CAS  Google Scholar 

  70. Alarcon GS, Schrohenloher RE, Bartolucci AA, Ward JR, Williams HJ, Koopman WJ (1990) Suppression of rheumatoid factor production by methotrexate in patients with rheumatoid arthritis. Evidence for differential influences of therapy and clinical status on IgM and IgA rheumatoid factor expression. Arth Rheum 33: 1156–1161

    Article  CAS  Google Scholar 

  71. Spadaro A, Riccieri V, Sili Scavalli A, Taccari E, Zoppini A (1993) One year treatment with low dose methotrexate in rheumatoid arthritis: effect on class specific rheumatoid factors. Clin Rheumatol 12: 357–360

    Article  PubMed  CAS  Google Scholar 

  72. Spadaro A, Taccari E, Riccieri V, Sensi F, Sili Scavalli A, Zoppini A (1997) Relationship of soluble interleukin-2-receptor and interleukin-6 with class-specific rheumatoid factors during low-dose methotrexate treatment in rheumatoid arthritis. Rev Rheum Engl Ed 64: 89–94

    CAS  Google Scholar 

  73. Olsen NJ, Teal GP, Brooks RH (1991) IgM-rheumatoid factor and responses to second-line drugs in rheumatoid arthritis. Agents Actions 34: 169–171

    Article  PubMed  CAS  Google Scholar 

  74. Moore S, Ruska K, Peters L, Olsen NJ (1994) Associations of IgA and IgA-rheumatoid factor with disease features in patients with rheumatoid arthritis. Immunol Invest 23: 355–365

    Article  PubMed  CAS  Google Scholar 

  75. Olsen NJ, Callahan LF, Pincus T (1987) Immunologic studies of rheumatoid arthritis patients treated with methotrexate. Arth Rheum 30: 481–488

    Article  CAS  Google Scholar 

  76. Nesher G, Moore TM (1990) The in vitro effects of methotrexate on peripheral blood mononuclear cells: modulation by methyl donors and spermidine. Arth Rheum 33: 954–959

    Article  CAS  Google Scholar 

  77. Olsen NJ, Murray LM (1989) Antiproliferative effects of methotrexate on peripheral blood mononuclear cells. Arth Rheum 32: 378–385

    Article  CAS  Google Scholar 

  78. Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP (1998) Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 102: 322–328

    Article  PubMed  CAS  Google Scholar 

  79. Segal R, Mozes E, Yaron M, Tartakovsky B (1989) The effects of methotrexate on the production and activity of interleukin-1. Arth Rheum 32: 370–377

    Article  CAS  Google Scholar 

  80. Moreland LW, Pratt PW, Mayes MD, Postlethwaite A, Weisman MH, Schnitzer T, Lightfoot R, Calabrese L, Zelinger DJ, Woody JN, et al (1995) Double-blind, placebo-controlled multicenter trial using chimeric monoclonal anti-CD4 antibody, cM-T412, in rheumatoid arthritis patients receiving concomitant methotrexate. Arth Rheum 38: 1581–1588

    Article  CAS  Google Scholar 

  81. van der Lubbe PA, Dijkmans BA, Markusse HM, Nassander U, Breedveld FC (1995) A randomized, double-blind, placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis. Arth Rheum 38: 1097–1106

    Article  Google Scholar 

  82. Weinblatt ME, Trentham DE, Fraser PA, Holdsworth DE, Falchuk KR, Weissman BN, Coblyn JS (1988) Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arth Rheum 31: 167–175

    Article  CAS  Google Scholar 

  83. Wascher TC, Hermann J, Brezinschek HP, Brezinschek R, Wilders-Truschnig M, Rainer F, Krejs GJ (1994) Cell-type specific response of peripheral blood lymphocytes to methotrexate in the treatment of rheumatoid arthritis. Clin Invest 72: 535–540

    Article  CAS  Google Scholar 

  84. Sperling RI, Coblyn JS, Larkin JK, Benincaso AI, Austen KF, Weinblatt ME (1990) Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate. Arth Rheum 33: 1149–1155

    Article  CAS  Google Scholar 

  85. Sperling RI, Benincaso AI, Anderson RJ, Coblyn JS, Austen KF, Weinblatt ME (1992) Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arth Rheum 35: 376–384

    Article  CAS  Google Scholar 

  86. Leroux JL, Damon M, Chavis C, Paulet A rastes de, Blotman F (1992) Effects of a single dose of methotrexate on 5- and 12-lipoxygenase products in patients with rheumatoid arthritis. J Rheum 19: 863–866

    PubMed  CAS  Google Scholar 

  87. Hawkes JS, Cleland LG, Proudman SM, James MJ (1994) The effect of methotrexate on ex vivo lipoxygenase metabolism in neutrophils from patients with rheumatoid arthritis. J Rheum 21: 55–58

    PubMed  CAS  Google Scholar 

  88. Kremer JM, Jubiz W, Michalek A, Rynes RI, Bartholomew LE, Bigaouette J, Tim-chalk M, Beeler D, Lininger L (1987) Fish-oil fatty acid supplementation in active rheumatoid arthritis. A double-blinded, controlled, crossover study. Ann Intern Med 106: 497–503

    PubMed  CAS  Google Scholar 

  89. Kremer JM, Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, Bartholomew LE, Sherman M (1990) Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. Arth Rheum 33: 810–820

    Article  CAS  Google Scholar 

  90. Maini RN, Elliott MJ, Brennan FM, Williams RO, Chu CQ, Paleolog E, Charles PJ, Taylor PC, Feldmann M (1995) Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease. [Review]. Immunol Rev 144: 195–223

    Article  PubMed  CAS  Google Scholar 

  91. Johnson WJ, DiMartino MJ, Meunier PC, Muirhead KA, Hanna N (1988) Methotrexate inhibits macrophage activation as well as vascular and cellular inflammatory events in rat adjuvant induced arthritis. JRheumatol 15: 745–749

    CAS  Google Scholar 

  92. DiMartino MJ, Johnson WJ, Votta B, Hanna N (1987) Effect of antiarthritic drugs on the enhanced interleukin-1 (IL-1) production by macrophages from adjuvant-induced arthritic (AA) rats. Agents Actions 21: 348–350

    Article  Google Scholar 

  93. Novaes GS, Mello SB, Laurindo IM, Cossermelli W (1996) Low dose methotrexate decreases intraarticular prostaglandin and interleukin 1 levels in antigen induced arthritis in rabbits. JRheumatol 23: 2092–2097

    CAS  Google Scholar 

  94. Segal R, Mozes E, Yaron M, Tartakovsky B (1989) The effects of methotrexate on the production and activity of interleukin-1. Arth Rheum 32: 370–377

    Article  CAS  Google Scholar 

  95. Chang DM, Baptiste P, Schur PH (1990) The effect of antirheumatic drugs on interleukin 1 (IL-1) activity and IL-1 and IL-1 inhibitor production by human monocytes. JRheumatol 17: 1148–1157

    CAS  Google Scholar 

  96. Brody M, Bohm I, Bauer R (1993) Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem 31: 667–674

    PubMed  CAS  Google Scholar 

  97. Tishler M, Caspi D, Graff E, Segal R, Peretz H, Yaron M (1989) Synovial and serum levels of methotrexate during methotrexate therapy of rheumatoid arthritis. Br J Rheumatol 28: 422–423

    Article  PubMed  CAS  Google Scholar 

  98. Chang DM, Weinblatt ME, Schur PH (1992) The effects of methotrexate on interleukin 1 in patients with rheumatoid arthritis. JRheumatol 19: 1678–1682

    CAS  Google Scholar 

  99. Bondeson J (1997) The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis on macrophage signal transduction and the induction of pro-inflammatory cytokines. Gen Pharmacol 29: 127–150

    Article  PubMed  CAS  Google Scholar 

  100. Williams AS, Punn YL, Amos N, Cooper AM, Williams BD (1995) The effect of liposomally conjugated methotrexate upon mediator release from human peripheral blood monocytes. Br JRheumatol 34: 241–245

    Article  CAS  Google Scholar 

  101. Williams AS, Topley N, Williams BD (1994) Effect of liposomally encapsulated MTXDMPE conjugates upon TNF alpha and PGE2 release by lipopolysaccharide stimulated rat peritoneal macrophages. Biochim Biophys Acta 1225: 217–222

    Article  PubMed  CAS  Google Scholar 

  102. Williams AS, Camilleri JP, Topley N, Williams BD (1994) Prostaglandin and tumor necrosis factor secretion by peritoneal macrophages isolated from normal and arthritic rats treated with liposomal methotrexate. J Pharmacol Toxicol Methods 32: 53–58

    Article  PubMed  CAS  Google Scholar 

  103. Smith-Oliver T, Noel LS, Stimpson SS, Yarnall DP, Connolly KM (1993) Elevated levels of TNF in the joints of adjuvant arthritic rats. Cytokine 5: 298–304

    Article  PubMed  CAS  Google Scholar 

  104. Neurath MF, Hildner K, Becker C, Schlaak JF, Barbulescu K, Germann T, Schmitt E, Schirmacher P, Haralambous S, Pasparakis M, et al (1999) Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexate-mediated immunosuppression. Clin Exp Immunol 115: 42–55

    Article  PubMed  CAS  Google Scholar 

  105. Dolhain RJ, Tak PP, Dijkmans BA, De Kuiper P, Breedveld FC, Miltenburg AM (1998) Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis. Br JRheumatol 37: 502–508

    Article  CAS  Google Scholar 

  106. Barrera P, Boerbooms AM, Janssen EM, Sauerwein RW, Gallati H, Mulder J, de Boo T, Demacker PN, van de Putte LB, van der Meer JW (1993) Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy [see comments]. Arth Rheum 36: 1070–1079

    Article  CAS  Google Scholar 

  107. Crilly A, Mclnness IB, McDonald AG, Watson J, Capell HA, Madhok R (1995) Interleukin 6 (IL-6) and soluble IL-2 receptor levels in patients with rheumatoid arthritis treated with low dose oral methotrexate. JRheumatol 22: 224–226

    CAS  Google Scholar 

  108. Barrera P, Haagsma CJ, Boerbooms AMT, van Riel PLC, Borm GF, van de Putte LBA, van Der Meer JWM (1995) Effect of methotrexate alone or in combination with sulphasalazine on the production and circulating concentrations of cytokines and their antagonists. Longitudinal evaluation in patients with rheumatoid arthritis. Br J Rheumatol 34: 747–755

    Article  PubMed  CAS  Google Scholar 

  109. Barrera P, Boerbooms AM, Sauerwein RW, Demacker PN, van de Putte LB, van der Meer JW (1994) Interference of circulating azathioprine but not methotrexate or sulfasalazine with measurements of interleukin-6 bioactivity. Lymphokine Cytokine Res 13: 155–159

    PubMed  CAS  Google Scholar 

  110. Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, Baggiolini M, Gerber NJ (1995) Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol 34: 602–609

    Article  PubMed  CAS  Google Scholar 

  111. Loetscher P, Dewald B, Baggiolini M, Seitz M (1994) Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes. Effects of anti-rheumatic drugs. Cytokine 6: 162–170

    Article  PubMed  CAS  Google Scholar 

  112. Constantin A, Loubet-Lescoulie P, Lambert N, Yassine-Diab B, Abbal M, Mazieres B, de Preval C, Cantagrel A (1998) Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis: evidence of increased interleukin-4 and interleukin-10 gene expression demonstrated in vitro by competitive reverse transcriptasepolymerase chain reaction. Arth Rheum 41: 48–57

    Article  CAS  Google Scholar 

  113. Merrill JT, Shen C, Schreibman D, Coffey D, Zakharenko O, Fisher R, Lahita RG, Salmon J, Cronstein BN (1997) Adenosine A, receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arth Rheum 40: 1308–1315

    CAS  Google Scholar 

  114. Heenen M, Laporte M, Noel JC, de Graef C (1998) Methotrexate induces apoptotic cell death in human keratinocytes. Arch Dermatol Res 290: 240–245

    Article  PubMed  CAS  Google Scholar 

  115. Said S, Jeffes EW, Weinstein GD (1997) Methotrexate. Clin Dermatol 15: 781–797

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. New York University School of Medicine, 550 First Ave., New York, NY, 10016, USA

    Bruce N. Cronstein & Edwin S. L. Chan

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  1. Bruce N. Cronstein
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  2. Edwin S. L. Chan
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  1. Division of Rheumatology, New York University Medical Center, 550 First Avenue, New York, NY, 10016, USA

    Bruce N. Cronstein

  2. Programm in Molecular and Pharmacologic Therapeutics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021-6094, USA

    Joseph R. Bertino

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Cronstein, B.N., Chan, E.S.L. (2000). The mechanisms of methotrexate’s action in the treatment of inflammatory disease. In: Cronstein, B.N., Bertino, J.R. (eds) Methotrexate. Milestones in Drug Therapy. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8452-5_5

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  • DOI: https://doi.org/10.1007/978-3-0348-8452-5_5

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9573-6

  • Online ISBN: 978-3-0348-8452-5

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