Skip to main content
PMC home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 1994 May;53(5):315–322. doi: 10.1136/ard.53.5.315

Intramuscular gold decreases cytokine expression and macrophage numbers in the rheumatoid synovial membrane.

G Yanni 1, M Nabil 1, M R Farahat 1, R N Poston 1, G S Panayi 1
PMCID: PMC1005330  PMID: 8017985

Abstract

OBJECTIVES--Cytokines, released from mononuclear cells (MNC) are mediators of joint destruction in rheumatoid arthritis (RA). The mechanisms of action of gold salts used in the treatment of RA are unknown. The aim of this study was to investigate cytokine expression and intensity of MNC infiltrate in the RA synovial membrane (SM) following treatment with sodium aurothiomalate (SAT). METHODS--Sequential blind needle biopsies were obtained at entry into the study and at two and 12 weeks after the start of SAT therapy in 10 patients with active RA. SMs were stained with a panel of monoclonal antibodies to assess cytokine expression (IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and GM-CSF). RESULTS--There was a significant decrease in IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha expression 12 weeks after treatment (p < 0.004, p < 0.002, p < 0.009 and p < 0.004 respectively). This was noted in the lining layer, the perivascular aggregates and the connective tissue areas. Detailed examination of the MNC infiltrate showed a significant reduction in inflammatory monocytes (MONO) in the lining layer at two weeks (p < 0.03). A decrease in the number of CD68+ macrophages (MAC) was noted in the perivascular and connective tissue areas at 12 weeks. No significant changes were observed in the number of T and B cells and blood vessels. CONCLUSION--The results suggest that gold may suppress RA disease activity by diminishing MONO and MAC numbers and consequently monokine production in the SM.

Full text

PDF
315

Images in this article

319Image
on p.319

Selected References

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

  1. Arend W. P., Joslin F. G., Massoni R. J. Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol. 1985 Jun;134(6):3868–3875. [PubMed] [Google Scholar]
  2. Arend W. P., Joslin F. G., Thompson R. C., Hannum C. H. An IL-1 inhibitor from human monocytes. Production and characterization of biologic properties. J Immunol. 1989 Sep 15;143(6):1851–1858. [PubMed] [Google Scholar]
  3. Arend W. P., Joslin F. G., Thompson R. C., Hannum C. H. An IL-1 inhibitor from human monocytes. Production and characterization of biologic properties. J Immunol. 1989 Sep 15;143(6):1851–1858. [PubMed] [Google Scholar]
  4. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  5. Balavoine J. F., de Rochemonteix B., Williamson K., Seckinger P., Cruchaud A., Dayer J. M. Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J Clin Invest. 1986 Oct;78(4):1120–1124. doi: 10.1172/JCI112669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barkley D. E., Feldmann M., Maini R. N. Cells with dendritic morphology and bright interleukin-1 alpha staining circulate in the blood of patients with rheumatoid arthritis. Clin Exp Immunol. 1990 Apr;80(1):25–31. doi: 10.1111/j.1365-2249.1990.tb06436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Becker S., Warren M. K., Haskill S. Colony-stimulating factor-induced monocyte survival and differentiation into macrophages in serum-free cultures. J Immunol. 1987 Dec 1;139(11):3703–3709. [PubMed] [Google Scholar]
  8. Beekhuizen H., Blokland I., Corsèl-van Tilburg A. J., Koning F., van Furth R. CD14 contributes to the adherence of human monocytes to cytokine-stimulated endothelial cells. J Immunol. 1991 Dec 1;147(11):3761–3767. [PubMed] [Google Scholar]
  9. Boraschi D., Volpini G., Villa L., Nencioni L., Scapigliati G., Nucci D., Antoni G., Matteucci G., Cioli F., Tagliabue A. A monoclonal antibody to the IL-1 beta peptide 163-171 blocks adjuvanticity but not pyrogenicity of IL-1 beta in vivo. J Immunol. 1989 Jul 1;143(1):131–134. [PubMed] [Google Scholar]
  10. Cavender D. E., Haskard D. O., Joseph B., Ziff M. Interleukin 1 increases the binding of human B and T lymphocytes to endothelial cell monolayers. J Immunol. 1986 Jan;136(1):203–207. [PubMed] [Google Scholar]
  11. Cavender D., Saegusa Y., Ziff M. Stimulation of endothelial cell binding of lymphocytes by tumor necrosis factor. J Immunol. 1987 Sep 15;139(6):1855–1860. [PubMed] [Google Scholar]
  12. Champion G. D., Graham G. G., Ziegler J. B. The gold complexes. Baillieres Clin Rheumatol. 1990 Dec;4(3):491–534. doi: 10.1016/s0950-3579(05)80005-6. [DOI] [PubMed] [Google Scholar]
  13. Corkill M. M., Kirkham B. W., Chikanza I. C., Gibson T., Panayi G. S. Intramuscular depot methylprednisolone induction of chrysotherapy in rheumatoid arthritis: a 24-week randomized controlled trial. Br J Rheumatol. 1990 Aug;29(4):274–279. doi: 10.1093/rheumatology/29.4.274. [DOI] [PubMed] [Google Scholar]
  14. Dinarello C. A., Thompson R. C. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today. 1991 Nov;12(11):404–410. doi: 10.1016/0167-5699(91)90142-G. [DOI] [PubMed] [Google Scholar]
  15. Dreher R. Origin of synovial type A cells during inflammation. An experimental approach. Immunobiology. 1982 Apr;161(3-4):232–245. doi: 10.1016/S0171-2985(82)80079-X. [DOI] [PubMed] [Google Scholar]
  16. Evans G. F., Zuckerman S. H. Pharmacologic modulation of TNF production by endotoxin stimulated macrophages: in vitro and in vivo effects of auranofin and other chrysotherapeutic compounds. Agents Actions. 1989 Mar;26(3-4):329–334. doi: 10.1007/BF01967297. [DOI] [PubMed] [Google Scholar]
  17. Firestein G. S., Berger A. E., Tracey D. E., Chosay J. G., Chapman D. L., Paine M. M., Yu C., Zvaifler N. J. IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol. 1992 Aug 1;149(3):1054–1062. [PubMed] [Google Scholar]
  18. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  19. Haynes D. R., Garrett I. R., Whitehouse M. W., Vernon-Roberts B. Do gold drugs inhibit interleukin-1? Evidence from an in vitro lymphocyte activating factor assay. J Rheumatol. 1988;15(5):775–778. [PubMed] [Google Scholar]
  20. Hirano T., Matsuda T., Hosoi K., Okano A., Matsui H., Kishimoto T. Absence of antiviral activity in recombinant B cell stimulatory factor 2 (BSF-2). Immunol Lett. 1988 Jan;17(1):41–45. doi: 10.1016/0165-2478(88)90099-5. [DOI] [PubMed] [Google Scholar]
  21. Hsu S. M., Ree H. J. Self-sandwich method. An improved immunoperoxidase technic for the detection of small amounts of antigens. Am J Clin Pathol. 1980 Jul;74(1):32–40. doi: 10.1093/ajcp/74.1.32. [DOI] [PubMed] [Google Scholar]
  22. Koch A. E., Polverini P. J., Leibovich S. J. Stimulation of neovascularization by human rheumatoid synovial tissue macrophages. Arthritis Rheum. 1986 Apr;29(4):471–479. doi: 10.1002/art.1780290403. [DOI] [PubMed] [Google Scholar]
  23. Lipsky P. E., Ziff M. Inhibition of antigen- and mitogen-induced human lymphocyte proliferation by gold compounds. J Clin Invest. 1977 Mar;59(3):455–466. doi: 10.1172/JCI108660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Littman B. H., Carlson P. L., Loose L. D., Sanders K. M. Effects of gold sodium thiomalate and tenidap sodium (CP-66,248-2) on a model of macrophage differentiation using HL-60 cells. Arthritis Rheum. 1990 Jan;33(1):29–36. doi: 10.1002/art.1780330104. [DOI] [PubMed] [Google Scholar]
  25. Littman B. H., Hall R. E. Effects of gold sodium thiomalate on functional correlates of human monocyte maturation. Arthritis Rheum. 1985 Dec;28(12):1384–1392. doi: 10.1002/art.1780281211. [DOI] [PubMed] [Google Scholar]
  26. Littman B. H., Schwartz P. Gold inhibition of the production of the second complement component by lymphokine-stimulated human monocytes. Arthritis Rheum. 1982 Mar;25(3):288–296. doi: 10.1002/art.1780250306. [DOI] [PubMed] [Google Scholar]
  27. Mangan D. F., Wahl S. M. Differential regulation of human monocyte programmed cell death (apoptosis) by chemotactic factors and pro-inflammatory cytokines. J Immunol. 1991 Nov 15;147(10):3408–3412. [PubMed] [Google Scholar]
  28. Mangan D. F., Welch G. R., Wahl S. M. Lipopolysaccharide, tumor necrosis factor-alpha, and IL-1 beta prevent programmed cell death (apoptosis) in human peripheral blood monocytes. J Immunol. 1991 Mar 1;146(5):1541–1546. [PubMed] [Google Scholar]
  29. Mapp P. I., Revell P. A. Ultrastructural characterisation of macrophages (type A cells) in the synovial lining. Rheumatol Int. 1988;8(4):171–176. doi: 10.1007/BF00270456. [DOI] [PubMed] [Google Scholar]
  30. Revell P. A. Synovial lining cells. Rheumatol Int. 1989;9(2):49–51. doi: 10.1007/BF00270244. [DOI] [PubMed] [Google Scholar]
  31. Ritchie D. M., Boyle J. A., McInnes J. M., Jasani M. K., Dalakos T. G., Grieveson P., Buchanan W. W. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med. 1968 Jul;37(147):393–406. [PubMed] [Google Scholar]
  32. Rooney M., Whelan A., Feighery C., Bresnihan B. Changes in lymphocyte infiltration of the synovial membrane and the clinical course of rheumatoid arthritis. Arthritis Rheum. 1989 Apr;32(4):361–369. doi: 10.1002/anr.1780320402. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Sanders K. M., Carlson P. L., Littman B. H. Effects of gold sodium thiomalate on interferon stimulation of C2 synthesis and HLA-DR expression by human monocytes. Arthritis Rheum. 1987 Sep;30(9):1032–1039. doi: 10.1002/art.1780300910. [DOI] [PubMed] [Google Scholar]
  35. Seckinger P., Lowenthal J. W., Williamson K., Dayer J. M., MacDonald H. R. A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol. 1987 Sep 1;139(5):1546–1549. [PubMed] [Google Scholar]
  36. Smith R. J., Chin J. E., Sam L. M., Justen J. M. Biologic effects of an interleukin-1 receptor antagonist protein on interleukin-1-stimulated cartilage erosion and chondrocyte responsiveness. Arthritis Rheum. 1991 Jan;34(1):78–83. doi: 10.1002/art.1780340112. [DOI] [PubMed] [Google Scholar]
  37. Soden M., Rooney M., Whelan A., Feighery C., Bresnihan B. Immunohistological analysis of the synovial membrane: search for predictors of the clinical course in rheumatoid arthritis. Ann Rheum Dis. 1991 Oct;50(10):673–676. doi: 10.1136/ard.50.10.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Thorpe R., Wadhwa M., Gearing A., Mahon B., Poole S. Sensitive and specific immunoradiometric assays for human interleukin-1 alpha. Lymphokine Res. 1988 Summer;7(2):119–127. [PubMed] [Google Scholar]
  39. Walters M. T., Smith J. L., Moore K., Evans P. R., Cawley M. I. An investigation of the action of disease modifying antirheumatic drugs on the rheumatoid synovial membrane: reduction in T lymphocyte subpopulations and HLA-DP and DQ antigen expression after gold or penicillamine therapy. Ann Rheum Dis. 1987 Jan;46(1):7–16. doi: 10.1136/ard.46.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wood N. C., Dickens E., Symons J. A., Duff G. W. In situ hybridization of interleukin-1 in CD14-positive cells in rheumatoid arthritis. Clin Immunol Immunopathol. 1992 Mar;62(3):295–300. doi: 10.1016/0090-1229(92)90106-x. [DOI] [PubMed] [Google Scholar]
  41. Zwadlo G., Schlegel R., Sorg C. A monoclonal antibody to a subset of human monocytes found only in the peripheral blood and inflammatory tissues. J Immunol. 1986 Jul 15;137(2):512–518. [PubMed] [Google Scholar]
  42. Zwadlo G., Voegeli R., Schulze Osthoff K., Sorg C. A monoclonal antibody to a novel differentiation antigen on human macrophages associated with the down-regulatory phase of the inflammatory process. Exp Cell Biol. 1987;55(6):295–304. doi: 10.1159/000163432. [DOI] [PubMed] [Google Scholar]

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

RESOURCES