Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2001 Aug;60(8):729–735. doi: 10.1136/ard.60.8.729

Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis

M CUTOLO 1, A SULLI 1, C PIZZORNI 1, B SERIOLO 1, R STRAUB 1
PMCID: PMC1753808  PMID: 11454634

Full Text

The Full Text of this article is available as a PDF (175.4 KB).

Figure 1  .

Figure 1  

Open in a new tab

Adenosine increase by MTX and subsequent immunosuppression through adenosine receptors. (A) MTX inhibits both, conversion of GAR → FGAR and AICAR → FAICAR. However, inhibition of the second step is stronger, which results in accumulation of AICAR. (B) Accumulated AICAR inhibits AMP deaminase and adenosine deaminase (ADA), which increases adenosine-5'-P and adenosine (C). (D) Intracellular accumulation of adenosine-5'-P and adenosine results in an increase of these compounds in the extracellular space. Here, adenosine-5'-P is converted to adenosine, which binds to the specific receptor subtypes A1, A2a, and A2b (E). Probably, there will be a preponderance of the A2 receptor pathway, yielding an increase of cyclic adenosine monophosphate (cAMP) in the cell (F). (G) cAMP increase leads to immunosuppression. AMP = adenosine-5'-monophosphate; MTX = methotrexate.

Figure 2  .

Figure 2  

Open in a new tab

Anti-inflammatory effects exerted by low dose MTX at the level of the synovial tissue in RA. (A) MTX reduces monocytic cell growth and increases their apoptosis. (B) MTX decreases the IL1 and IL6 secretion and increases IL1ra production. At the same time, MTX increases IL4 and IL10 gene expression and decreases gene expression of proinflammatory Th1 cytokines (IL2 and IFNγ). (C) MTX seems to exert indirect inhibition of COX-2 synthesis and neutrophil chemotaxis. (D) MTX exerts indirect inhibitory effects (through modulation of cytokines) on synovial metalloproteinase (MMP) production and stimulates their inhibitors (TIMP) (E). MTX = methotrexate; IL1ra = interleukin-1 receptor antagonist; IFNγ = interferon γ; COX-2 = cyclo-oxygenase-2; MMP = metalloproteinase; TIMP = tissue inhibitor of metalloproteinase.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allegra C. J., Chabner B. A., Drake J. C., Lutz R., Rodbard D., Jolivet J. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem. 1985 Aug 15;260(17):9720–9726. [PubMed] [Google Scholar]
  2. Allegra C. J., Drake J. C., Jolivet J., Chabner B. A. Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc Natl Acad Sci U S A. 1985 Aug;82(15):4881–4885. doi: 10.1073/pnas.82.15.4881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Andersen P. A., West S. G., O'Dell J. R., Via C. S., Claypool R. G., Kotzin B. L. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med. 1985 Oct;103(4):489–496. doi: 10.7326/0003-4819-103-4-489. [DOI] [PubMed] [Google Scholar]
  4. Armstrong M. A., Shah S., Hawkins S. A., Bell A. L., Roberts S. D. Reduction of monocyte 5'nucleotidase activity by gamma-interferon in multiple sclerosis and autoimmune diseases. Ann Neurol. 1988 Jul;24(1):12–16. doi: 10.1002/ana.410240104. [DOI] [PubMed] [Google Scholar]
  5. Baugh C. M., Krumdieck C. L., Nair M. G. Polygammaglutamyl metabolites of methotrexate. Biochem Biophys Res Commun. 1973 May 1;52(1):27–34. doi: 10.1016/0006-291x(73)90949-2. [DOI] [PubMed] [Google Scholar]
  6. Bookbinder S. A., Espinoza L. R., Fenske N. A., Germain B. F., Vasey F. B. Methotrexate: its use in the rheumatic diseases. Clin Exp Rheumatol. 1984 Apr-Jun;2(2):185–193. [PubMed] [Google Scholar]
  7. Bouma M. G., Stad R. K., van den Wildenberg F. A., Buurman W. A. Differential regulatory effects of adenosine on cytokine release by activated human monocytes. J Immunol. 1994 Nov 1;153(9):4159–4168. [PubMed] [Google Scholar]
  8. Bressolle F., Kinowski J. M., Morel J., Pouly B., Sany J., Combe B. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol. 2000 Sep;27(9):2110–2114. [PubMed] [Google Scholar]
  9. Brody M., Böhm I., Bauer R. 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. 1993 Oct;31(10):667–674. doi: 10.1515/cclm.1993.31.10.667. [DOI] [PubMed] [Google Scholar]
  10. Cauli A., Yanni G., Panayi G. S. Interleukin-1, interleukin-1 receptor antagonist and macrophage populations in rheumatoid arthritis synovial membrane. Br J Rheumatol. 1997 Sep;36(9):935–940. doi: 10.1093/rheumatology/36.9.935. [DOI] [PubMed] [Google Scholar]
  11. Christensen L. D., Andersen V., Nygaard P., Bendtzen K. Effects of immunomodulators on ecto-5'-nucleotidase activity on blood mononuclear cells in vitro. Scand J Immunol. 1992 Apr;35(4):407–413. doi: 10.1111/j.1365-3083.1992.tb02875.x. [DOI] [PubMed] [Google Scholar]
  12. Connolly K. M., Stecher V. J., Danis E., Pruden D. J., LaBrie T. Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate. Int J Immunopharmacol. 1988;10(6):717–728. doi: 10.1016/0192-0561(88)90025-2. [DOI] [PubMed] [Google Scholar]
  13. Crilly A., McInness I. B., McDonald A. G., Watson J., Capell H. A., Madhok R. Interleukin 6 (IL-6) and soluble IL-2 receptor levels in patients with rheumatoid arthritis treated with low dose oral methotrexate. J Rheumatol. 1995 Feb;22(2):224–226. [PubMed] [Google Scholar]
  14. Cronstein B. N., Eberle M. A., Gruber H. E., Levin R. I. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2441–2445. doi: 10.1073/pnas.88.6.2441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cronstein B. N., Naime D., Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest. 1993 Dec;92(6):2675–2682. doi: 10.1172/JCI116884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cronstein B. N. The mechanism of action of methotrexate. Rheum Dis Clin North Am. 1997 Nov;23(4):739–755. doi: 10.1016/s0889-857x(05)70358-6. [DOI] [PubMed] [Google Scholar]
  17. Cutolo M., Barone A., Accardo S., Setti M., Villaggio B. Effect of cyclosporin on apoptosis in human cultured monocytic THP-1 cells and synovial macrophages. Clin Exp Rheumatol. 1998 Jul-Aug;16(4):417–422. [PubMed] [Google Scholar]
  18. Cutolo M., Bisso A., Sulli A., Felli L., Briata M., Pizzorni C., Villaggio B. Antiproliferative and antiinflammatory effects of methotrexate on cultured differentiating myeloid monocytic cells (THP-1) but not on synovial macrophages from patients with rheumatoid arthritis. J Rheumatol. 2000 Nov;27(11):2551–2557. [PubMed] [Google Scholar]
  19. Cutolo M. Macrophages as effectors of the immunoendocrinologic interactions in autoimmune rheumatic diseases. Ann N Y Acad Sci. 1999 Jun 22;876:32–42. doi: 10.1111/j.1749-6632.1999.tb07620.x. [DOI] [PubMed] [Google Scholar]
  20. Edwards N. L., Magilavy D. B., Cassidy J. T., Fox I. H. Lymphocyte ecto-5'-nucleotidase deficiency in agammaglobulinemia. Science. 1978 Aug 18;201(4356):628–630. doi: 10.1126/science.27864. [DOI] [PubMed] [Google Scholar]
  21. Figueíredo F., Uhing R. J., Okonogi K., Gettys T. W., Johnson S. P., Adams D. O., Prpic V. Activation of the cAMP cascade inhibits an early event involved in murine macrophage Ia expression. J Biol Chem. 1990 Jul 25;265(21):12317–12323. [PubMed] [Google Scholar]
  22. Firestein G. S., Paine M. M., Boyle D. L. Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arthritis Rheum. 1994 Feb;37(2):193–200. doi: 10.1002/art.1780370207. [DOI] [PubMed] [Google Scholar]
  23. Frenia M. L., Long K. S. Methotrexate and nonsteroidal antiinflammatory drug interactions. Ann Pharmacother. 1992 Feb;26(2):234–237. doi: 10.1177/106002809202600219. [DOI] [PubMed] [Google Scholar]
  24. Friesen C., Herr I., Krammer P. H., Debatin K. M. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med. 1996 May;2(5):574–577. doi: 10.1038/nm0596-574. [DOI] [PubMed] [Google Scholar]
  25. GUBNER R., AUGUST S., GINSBERG V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci. 1951 Feb;221(2):176–182. [PubMed] [Google Scholar]
  26. Genestier L., Paillot R., Fournel S., Ferraro C., Miossec P., Revillard J. P. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest. 1998 Jul 15;102(2):322–328. doi: 10.1172/JCI2676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Griffith S. M., Fisher J., Clarke S., Montgomery B., Jones P. W., Saklatvala J., Dawes P. T., Shadforth M. F., Hothersall T. E., Hassell A. B. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford) 2000 Oct;39(10):1102–1109. doi: 10.1093/rheumatology/39.10.1102. [DOI] [PubMed] [Google Scholar]
  28. Groff G. D., Shenberger K. N., Wilke W. S., Taylor T. H. Low dose oral methotrexate in rheumatoid arthritis: an uncontrolled trial and review of the literature. Semin Arthritis Rheum. 1983 May;12(4):333–347. doi: 10.1016/0049-0172(83)90014-8. [DOI] [PubMed] [Google Scholar]
  29. Gruber H. E., Hoffer M. E., McAllister D. R., Laikind P. K., Lane T. A., Schmid-Schoenbein G. W., Engler R. L. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury. Circulation. 1989 Nov;80(5):1400–1411. doi: 10.1161/01.cir.80.5.1400. [DOI] [PubMed] [Google Scholar]
  30. Haraoui B., Pelletier J. P., Cloutier J. M., Faure M. P., Martel-Pelletier J. Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis. In vivo effects of antirheumatic drugs. Arthritis Rheum. 1991 Feb;34(2):153–163. doi: 10.1002/art.1780340205. [DOI] [PubMed] [Google Scholar]
  31. Haskó G., Németh Z. H., Vizi E. S., Salzman A. L., Szabó C. An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotoxemic mice. Eur J Pharmacol. 1998 Oct 9;358(3):261–268. doi: 10.1016/s0014-2999(98)00619-0. [DOI] [PubMed] [Google Scholar]
  32. Haskó G., Szabó C., Németh Z. H., Kvetan V., Pastores S. M., Vizi E. S. Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J Immunol. 1996 Nov 15;157(10):4634–4640. [PubMed] [Google Scholar]
  33. Hoffmeister R. T. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med. 1983 Dec 30;75(6A):69–73. doi: 10.1016/0002-9343(83)90477-1. [DOI] [PubMed] [Google Scholar]
  34. Hornung N., Stengaard-Pedersen K., Ehrnrooth E., Ellingsen T., Poulsen J. H. The effects of low-dose methotrexate on thymidylate synthetase activity in human peripheral blood mononuclear cells. Clin Exp Rheumatol. 2000 Nov-Dec;18(6):691–698. [PubMed] [Google Scholar]
  35. Hu S. K., Mitcho Y. L., Oronsky A. L., Kerwar S. S. Studies on the effect of methotrexate on macrophage function. J Rheumatol. 1988 Feb;15(2):206–209. [PubMed] [Google Scholar]
  36. Huschtscha L. I., Bartier W. A., Ross C. E., Tattersall M. H. Characteristics of cancer cell death after exposure to cytotoxic drugs in vitro. Br J Cancer. 1996 Jan;73(1):54–60. doi: 10.1038/bjc.1996.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Janson R. W., Hance K. R., Arend W. P. Production of IL-1 receptor antagonist by human in vitro-derived macrophages. Effects of lipopolysaccharide and granulocyte-macrophage colony-stimulating factor. J Immunol. 1991 Dec 15;147(12):4218–4223. [PubMed] [Google Scholar]
  38. Jobanputra P., Hunter M., Clark D., Lambert C. M., Hurst N. P. An audit of methotrexate and folic acid for rheumatoid arthritis. Experience from a teaching centre. Br J Rheumatol. 1995 Oct;34(10):971–975. doi: 10.1093/rheumatology/34.10.971. [DOI] [PubMed] [Google Scholar]
  39. Johnson W. J., DiMartino M. J., Meunier P. C., Muirhead K. A., Hanna N. Methotrexate inhibits macrophage activation as well as vascular and cellular inflammatory events in rat adjuvant induced arthritis. J Rheumatol. 1988;15(5):745–749. [PubMed] [Google Scholar]
  40. Karim A., Tolbert D. S., Hunt T. L., Hubbard R. C., Harper K. M., Geis G. S. Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol. 1999 Dec;26(12):2539–2543. [PubMed] [Google Scholar]
  41. Koshiba M., Kojima H., Huang S., Apasov S., Sitkovsky M. V. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem. 1997 Oct 10;272(41):25881–25889. doi: 10.1074/jbc.272.41.25881. [DOI] [PubMed] [Google Scholar]
  42. Kraan M. C., de Koster B. M., Elferink J. G., Post W. J., Breedveld F. C., Tak P. P. Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients. Arthritis Rheum. 2000 Jul;43(7):1488–1495. doi: 10.1002/1529-0131(200007)43:7<1488::AID-ANR11>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  43. Kremer J. M., Hamilton R. A. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol. 1995 Nov;22(11):2072–2077. [PubMed] [Google Scholar]
  44. Kremer J. M. The mechanism of action of methotrexate in rheumatoid arthritis: the search continues. J Rheumatol. 1994 Jan;21(1):1–5. [PubMed] [Google Scholar]
  45. Lazdins J., Karnovsky M. L. Effect of phosphate esters, nucleotides and nucleosides on 5'-nucleotidase of cultured mouse macrophages. J Cell Physiol. 1978 Jul;96(1):115–122. doi: 10.1002/jcp.1040960114. [DOI] [PubMed] [Google Scholar]
  46. Leroux J. L., Damon M., Chavis C., Crastes De Paulet A., Blotman F. Effets du méthotrexate sur la synthèse de leucotriénes et de dérivés de la lipoxygénase par les polynucléaires au cours de la polyarthrite rhumatoïde. Rev Rhum Mal Osteoartic. 1992 Oct;59(9):587–591. [PubMed] [Google Scholar]
  47. Link A. A., Kino T., Worth J. A., McGuire J. L., Crane M. L., Chrousos G. P., Wilder R. L., Elenkov I. J. Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol. 2000 Jan 1;164(1):436–442. doi: 10.4049/jimmunol.164.1.436. [DOI] [PubMed] [Google Scholar]
  48. MacNaul K. L., Chartrain N., Lark M., Tocci M. J., Hutchinson N. I. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin-1 and tumor necrosis factor-alpha on stromelysin expression. J Biol Chem. 1990 Oct 5;265(28):17238–17245. [PubMed] [Google Scholar]
  49. Martel-Pelletier J., Cloutier J. M., Pelletier J. P. In vivo effects of antirheumatic drugs on neutral collagenolytic proteases in human rheumatoid arthritis cartilage and synovium. J Rheumatol. 1988 Aug;15(8):1198–1204. [PubMed] [Google Scholar]
  50. Mazzoni M. R., Martini C., Lucacchini A. Regulation of agonist binding to A2A adenosine receptors: effects of guanine nucleotides (GDP[S] and GTP[S]) and Mg2+ ion. Biochim Biophys Acta. 1993 Dec 16;1220(1):76–84. doi: 10.1016/0167-4889(93)90100-4. [DOI] [PubMed] [Google Scholar]
  51. Mello S. B., Barros D. M., Silva A. S., Laurindo I. M., Novaes G. S. Methotrexate as a preferential cyclooxygenase 2 inhibitor in whole blood of patients with rheumatoid arthritis. Rheumatology (Oxford) 2000 May;39(5):533–536. doi: 10.1093/rheumatology/39.5.533. [DOI] [PubMed] [Google Scholar]
  52. Merrill J. T., Shen C., Schreibman D., Coffey D., Zakharenko O., Fisher R., Lahita R. G., Salmon J., Cronstein B. N. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum. 1997 Jul;40(7):1308–1315. doi: 10.1002/1529-0131(199707)40:7<1308::AID-ART16>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  53. Michaels R. M., Nashel D. J., Leonard A., Sliwinski A. J., Derbes S. J. Weekly intravenous methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum. 1982 Mar;25(3):339–341. doi: 10.1002/art.1780250312. [DOI] [PubMed] [Google Scholar]
  54. Miossec P., Briolay J., Dechanet J., Wijdenes J., Martinez-Valdez H., Banchereau J. Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum. 1992 Aug;35(8):874–883. doi: 10.1002/art.1780350805. [DOI] [PubMed] [Google Scholar]
  55. Montesinos M. C., Yap J. S., Desai A., Posadas I., McCrary C. T., Cronstein B. N. Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis. Arthritis Rheum. 2000 Mar;43(3):656–663. doi: 10.1002/1529-0131(200003)43:3<656::AID-ANR23>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  56. Morabito L., Montesinos M. C., Schreibman D. M., Balter L., Thompson L. F., Resta R., Carlin G., Huie M. A., Cronstein B. N. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest. 1998 Jan 15;101(2):295–300. doi: 10.1172/JCI1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Morgan S. L., Baggott J. E., Vaughn W. H., Austin J. S., Veitch T. A., Lee J. Y., Koopman W. J., Krumdieck C. L., Alarcón G. S. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994 Dec 1;121(11):833–841. doi: 10.7326/0003-4819-121-11-199412010-00002. [DOI] [PubMed] [Google Scholar]
  58. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  59. Nakashima-Matsushita N., Homma T., Yu S., Matsuda T., Sunahara N., Nakamura T., Tsukano M., Ratnam M., Matsuyama T. Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum. 1999 Aug;42(8):1609–1616. doi: 10.1002/1529-0131(199908)42:8<1609::AID-ANR7>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  60. Novogrodsky A., Patya M., Rubin A. L., Stenzel K. H. Agents that increase cellular cAMP inhibit production of interleukin-2, but not its activity. Biochem Biophys Res Commun. 1983 Jul 18;114(1):93–98. doi: 10.1016/0006-291x(83)91598-x. [DOI] [PubMed] [Google Scholar]
  61. Renz H., Gong J. H., Schmidt A., Nain M., Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol. 1988 Oct 1;141(7):2388–2393. [PubMed] [Google Scholar]
  62. Ritchie P. K., Spangelo B. L., Krzymowski D. K., Rossiter T. B., Kurth E., Judd A. M. Adenosine increases interleukin 6 release and decreases tumour necrosis factor release from rat adrenal zona glomerulosa cells, ovarian cells, anterior pituitary cells, and peritoneal macrophages. Cytokine. 1997 Mar;9(3):187–198. doi: 10.1006/cyto.1996.0153. [DOI] [PubMed] [Google Scholar]
  63. Rossi A. G., McCutcheon J. C., Roy N., Chilvers E. R., Haslett C., Dransfield I. Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J Immunol. 1998 Apr 1;160(7):3562–3568. [PubMed] [Google Scholar]
  64. Roux-Lombard P., Modoux C., Dayer J. M. Production of interleukin-1 (IL-1) and a specific IL-1 inhibitor during human monocyte-macrophage differentiation: influence of GM-CSF. Cytokine. 1989 Nov;1(1):45–51. doi: 10.1016/1043-4666(89)91047-8. [DOI] [PubMed] [Google Scholar]
  65. Sajjadi F. G., Takabayashi K., Foster A. C., Domingo R. C., Firestein G. S. Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. J Immunol. 1996 May 1;156(9):3435–3442. [PubMed] [Google Scholar]
  66. Savic V., Stefanovic V., Ardaillou N., Ardaillou R. Induction of ecto-5'-nucleotidase of rat cultured mesangial cells by interleukin-1 beta and tumour necrosis factor-alpha. Immunology. 1990 Jul;70(3):321–326. [PMC free article] [PubMed] [Google Scholar]
  67. Segal R., Caspi D., Tishler M., Wigler I., Yaron M. Short term effects of low dose methotrexate on the acute phase reaction in patients with rheumatoid arthritis. J Rheumatol. 1989 Jul;16(7):914–917. [PubMed] [Google Scholar]
  68. Seitz M., Dayer J. M. Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment. Rheumatology (Oxford) 2000 Jun;39(6):637–645. doi: 10.1093/rheumatology/39.6.637. [DOI] [PubMed] [Google Scholar]
  69. Seitz M., Loetscher P., Dewald B., Towbin H., Baggiolini M. In vitro modulation of cytokine, cytokine inhibitor, and prostaglandin E release from blood mononuclear cells and synovial fibroblasts by antirheumatic drugs. J Rheumatol. 1997 Aug;24(8):1471–1476. [PubMed] [Google Scholar]
  70. Seitz M., Loetscher P., Dewald B., Towbin H., Rordorf C., Gallati H., Baggiolini M., Gerber N. J. Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol. 1995 Jul;34(7):602–609. doi: 10.1093/rheumatology/34.7.602. [DOI] [PubMed] [Google Scholar]
  71. Seitz M., Loetscher P., Dewald B., Towbin H., Rordorf C., Gallati H., Gerber N. J. Interleukin 1 (IL-1) receptor antagonist, soluble tumor necrosis factor receptors, IL-1 beta, and IL-8--markers of remission in rheumatoid arthritis during treatment with methotrexate. J Rheumatol. 1996 Sep;23(9):1512–1516. [PubMed] [Google Scholar]
  72. Seitz M., Zwicker M., Loetscher P. Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes. Arthritis Rheum. 1998 Nov;41(11):2032–2038. doi: 10.1002/1529-0131(199811)41:11<2032::AID-ART19>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  73. Shiroky J. B. The use of folates concomitantly with low-dose pulse methotrexate. Rheum Dis Clin North Am. 1997 Nov;23(4):969–980. doi: 10.1016/s0889-857x(05)70369-0. [DOI] [PubMed] [Google Scholar]
  74. Smoleńska Z., Kaznowska Z., Zarówny D., Simmonds H. A., Smoleński R. T. Effect of methotrexate on blood purine and pyrimidine levels in patients with rheumatoid arthritis. Rheumatology (Oxford) 1999 Oct;38(10):997–1002. doi: 10.1093/rheumatology/38.10.997. [DOI] [PubMed] [Google Scholar]
  75. Snijdewint F. G., Kaliński P., Wierenga E. A., Bos J. D., Kapsenberg M. L. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol. 1993 Jun 15;150(12):5321–5329. [PubMed] [Google Scholar]
  76. Sonneveld P., Schultz F. W., Nooter K., Hählen K. Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate. Cancer Chemother Pharmacol. 1986;18(2):111–116. doi: 10.1007/BF00262278. [DOI] [PubMed] [Google Scholar]
  77. Steinsson K., Weinstein A., Korn J., Abeles M. Low dose methotrexate in rheumatoid arthritis. J Rheumatol. 1982 Nov-Dec;9(6):860–866. [PubMed] [Google Scholar]
  78. Straub R. H., Cutolo M. Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 2001 Mar;44(3):493–507. doi: 10.1002/1529-0131(200103)44:3<493::AID-ANR95>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  79. Straub R. H., Männel D. N. How the immune system puts the brain to sleep. Nat Med. 1999 Aug;5(8):877–879. doi: 10.1038/11315. [DOI] [PubMed] [Google Scholar]
  80. Straub R. H., Müller-Ladner U., Lichtinger T., Schölmerich J., Menninger H., Lang B. Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs. Br J Rheumatol. 1997 Dec;36(12):1298–1303. doi: 10.1093/rheumatology/36.12.1298. [DOI] [PubMed] [Google Scholar]
  81. Thompson R. N., Watts C., Edelman J., Esdaile J., Russell A. S. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol. 1984 Dec;11(6):760–763. [PubMed] [Google Scholar]
  82. Towbin H., Schmitz A., van Oostrum J., Seitz M., Dewald B., Zingel O., Motz J., Vosbeck K., Rordorf C. Monoclonal antibody based enzyme-linked and chemiluminescent assays for the human interleukin-1 receptor antagonist. Application to measure hIL-1ra levels in monocyte cultures and synovial fluids. J Immunol Methods. 1994 Mar 29;170(1):125–135. doi: 10.1016/0022-1759(94)90252-6. [DOI] [PubMed] [Google Scholar]
  83. Vergne P., Liagre B., Bertin P., Cook-Moreau J., Treves R., Beneytout J. L., Rigaud M. Methotrexate and cyclooxygenase metabolism in cultured human rheumatoid synoviocytes. J Rheumatol. 1998 Mar;25(3):433–440. [PubMed] [Google Scholar]
  84. Weinblatt M. E., Coblyn J. S., Fox D. A., Fraser P. A., Holdsworth D. E., Glass D. N., Trentham D. E. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985 Mar 28;312(13):818–822. doi: 10.1056/NEJM198503283121303. [DOI] [PubMed] [Google Scholar]
  85. Wilke W. S., Calabrese L. H., Scherbel A. L. Methotrexate in the treatment of rheumatoid arthritis; pilot study. Cleve Clin Q. 1980 Winter;47(4):305–309. doi: 10.3949/ccjm.47.4.305. [DOI] [PubMed] [Google Scholar]
  86. Williams H. J., Willkens R. F., Samuelson C. O., Jr, Alarcón G. S., Guttadauria M., Yarboro C., Polisson R. P., Weiner S. R., Luggen M. E., Billingsley L. M. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 1985 Jul;28(7):721–730. doi: 10.1002/art.1780280702. [DOI] [PubMed] [Google Scholar]
  87. Willkens R. F., Watson M. A., Paxson C. S. Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol. 1980 Jul-Aug;7(4):501–505. [PubMed] [Google Scholar]
  88. Xaus J., Mirabet M., Lloberas J., Soler C., Lluis C., Franco R., Celada A. IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. J Immunol. 1999 Mar 15;162(6):3607–3614. [PubMed] [Google Scholar]
  89. Zimmerman C. L., Franz T. J., Slattery J. T. Pharmacokinetics of the poly-gamma-glutamyl metabolites of methotrexate in skin and other tissues of rats and hairless mice. J Pharmacol Exp Ther. 1984 Nov;231(2):242–247. [PubMed] [Google Scholar]
  90. van Ede A. E., Laan R. F., Blom H. J., De Abreu R. A., van de Putte L. B. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum. 1998 Apr;27(5):277–292. doi: 10.1016/s0049-0172(98)80049-8. [DOI] [PubMed] [Google Scholar]
  91. van der Pouw Kraan T. C., Boeije L. C., Smeenk R. J., Wijdenes J., Aarden L. A. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med. 1995 Feb 1;181(2):775–779. doi: 10.1084/jem.181.2.775. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES