Rheumatology International

, Volume 9, Issue 6, pp 259–264 | Cite as

Absence of correlations between indices of systemic inflammation and synovial fluid interleukin 1 (alpha and beta) in rheumatic diseases

  • F. S. di Giovine
  • S. Poole
  • R. D. Situnayake
  • M. Wadhwa
  • G. W. Duff


There are two forms of the cytokine interleukin 1 (IL1), produced by two distinct genes encoding a neutral (IL1 beta) and an acidic (IL1 alpha) peptide. They have powerful pro-inflammatory, immunopotentiating, catabolic and arthritogenic properties in vivo and have been implicated in the pathogenesis of rheumatic diseases. In this study, using specific immunoassays, we have measured both IL1 alpha and IL1 beta levels in synovial fluids (SF) from a large number of patients with different rheumatic diseases. Biologically significant levels of both cytokines were found in SF from patients with different forms of arthritis, but no correlations were found with any of the measures of disease activity that we tested. We also describe the presence in joint exudates of biological inhibitor(s) that neutralize IL1-induced T-cell activation. This is the first report of IL1 alpha and IL1 beta measurements in the same synovial exudates and also of the comparison of local levels of these cytokines with conventional indices of systemic inflammation.

Key words

Arthritis Synovial fluids Interleukin 1 IL1 alpha IL1 beta Biological inhibitors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bodel P, Hollingsworth JW (1969) Pyrogen release from human synovial exudate cells. Br J Exp Pathol 49:11–19Google Scholar
  2. 2.
    Dayer JM, Russell RGG, Krane SM (1977) Collagenase production by rheumatoid synovial cells: stimulation by a human lymphocyte factor. Science 135:181–183Google Scholar
  3. 3.
    Oppenheim JJ, Kovacs EJ, Matsushima K, Durum SK (1986) There is more than one interleukin 1. Immunol Today 7:45–56Google Scholar
  4. 4.
    Beutler B, Cerami A (1986) Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 320:584–588Google Scholar
  5. 5.
    Lomedico P, Gubler U, Hellman CP, Dukovitch M, Giri JP, Pan YE, Collier K, Semionow R, Chua AO, Mizel SB (1984) Cloning and expression of murine interleukin 1 cDNA in Escherichia coli. Nature 312:458–462Google Scholar
  6. 6.
    March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, Conlon PJ, Hopp TP, Cosman D (1985) Cloning, sequence and expression of two distinct human interleukin 1 complementary cDNAs. Nature 315:641–647Google Scholar
  7. 7.
    Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA (1984) Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci USA 81:7807–7811Google Scholar
  8. 8.
    Dinarello CA (1986) Interleukin 1: aminoacid sequences, multiple biological activities and comparison with tumor necrosis factor (cachectin). Year Immunol 2:68–89Google Scholar
  9. 9.
    Dinarello CA (1984) Interleukin 1. Rev Infect Dis 6:51–95Google Scholar
  10. 10.
    Gery I, Gershon RK, Waksman BH (1972) Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J Exp Med 136:128–142Google Scholar
  11. 11.
    Darlington GJ, Wilson DR, Lachmann LB (1986) Monocyte-conditioned medium, interleukin 1 and tumour necrosis factor stimulate the acute phase response in human hepatoma cells in vitro. J Cell Biol 103:787–793Google Scholar
  12. 12.
    Mizel SB, Dayer JM, Krane SM, Mergenhagen SE (1981) Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte-activating factor (interleukin 1). Proc Natl Acad Sci USA 78:2474–2477Google Scholar
  13. 13.
    Gowen M, Wood DD, Ihrie EJ, McGuire MKB, Graham R, Russel RGG (1983) An interleukin 1-like factor stimulates bone resorption in vitro. Nature 306:378–380Google Scholar
  14. 14.
    Saklatvala J (1981) Characterization of catabolin, the major product of synovial tissue that induces resorption of cartilage proteoglycan in vitro. Biochem J 199:705–714Google Scholar
  15. 15.
    Hollingsworth JW, Atkins E (1965) Synovial inflammatory response to bacterial endotoxins. Yale J Biol Med 38:241–256Google Scholar
  16. 16.
    Pettipher ER, Higgs GA, Henderson B (1986) Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci USA 83:8749–8753Google Scholar
  17. 17.
    Durum SK, Schmidt JA, Oppenheim JJ (1985) Interleukin 1: an immunological perspective. Annu Rev Immunol 3:263–287Google Scholar
  18. 18.
    Fenton MJ, Clark BD, Collins KL, Webb AC, Rich A, Auron PE (1987) Transcriptional regulation of the human prointerleukin 1 beta gene. J Immunol 138:3972–3979Google Scholar
  19. 19.
    Clark BD, Fenton MJ, Rey HL, Webb AC, Auron PE (1988) Characterization of cis and trans acting elements involved in human pro-IL1 beta gene expression. In: Powanda MC, Oppenheim JJ, Kluger MJ, Dinarello CA (eds) Monokines and other non-lymphocytic cytokines. Liss, New York, pp 47–53Google Scholar
  20. 20.
    Di Giovine FS, Symons JA, Duff GW (1988) Protein/mRNA analysis of monokine production. Lymphokine Res (1.45 abstr.) 7:271Google Scholar
  21. 21.
    Fontana A, Hengartner H, Weber E, Fehr K, Grob PJ, Cohen G (1982) Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int 2:49–53Google Scholar
  22. 22.
    Wood DD, Ihrie EJ, Dinarello CA, Cohen P (1983) Isolation of an interleukin 1 like factor from human joint effusions. Arthritis Rheum 26:975–984Google Scholar
  23. 23.
    Kaye J, Gillis S, Mizel SB, Shevach EM, Malek TR, Dinarello CA, Lachman LB, Janeway CA (1984) Growth of a cloned helper T-cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. J Immunol 133:1339–1344Google Scholar
  24. 24.
    Di Giovine FS, Malawista SE, Nuki G, Duff GW (1987) Interleukin-1 (IL-1) as a mediator of crystal arthritis. Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL-1. J Immunol 138:3213–3218Google Scholar
  25. 25.
    Lisi JP, Chu CW, Koch GA, Endres S, Lonnemann G, Dinarello CA (1987) Development and use of a radioimmunoassay for human interleukin 1 beta. Lymphokine Res 6:229–244Google Scholar
  26. 26.
    Thorpe R, Wadhwa M, Gearing A, Mahon B, Poole S (1988) Sensitive and specific immunoradiometric assays for human interleukin 1 alpha. Lymphokine Res 7:119–127Google Scholar
  27. 27.
    Pryce-Jones RH, Wood RC (1975) Purification of granulocyte neutral proteinase from human blood and rheumatoid synovial fluid. Biochem Biophys Acta 397:449–458Google Scholar
  28. 28.
    Black RA, Kronheim SR et al (1988) Generation of biologically active interleukin 1 beta by proteolytic cleavage of the inactive precursor. J Biol Chem 263:9437–9442Google Scholar
  29. 29.
    Wood DD, Ihrie EJ, Hamerman D (1985) Release of interleukin 1 from synovial tissue in vitro. Arthritis Rheum 28:853–861Google Scholar
  30. 30.
    Ramsay C, di Giovine FS, Forster P, Nuki G, Duff GW (1986) Inhibition of IL1-driven T-cell mitogenesis by synovial exudate fluids from patients with RA and OA. Br J Rheumatol 25 (suppl 2):30Google Scholar
  31. 31.
    Lotz M, Tsoukas CD, Robinson CA, Dinarello CA, Carson DA, Vaughan JH (1986) Basis for defective responses of rheumatoid arthritis synovial fluid lymphocytes to anti CD3 antibodies. J Clin Invest 78:713–721Google Scholar
  32. 32.
    Liao Z, Grimshaw R, Rosenstreich DL (1984) Identification of a specific interleukin 1 inhibitor in the urine of febrile patients. J Exp Med 159:129–136Google Scholar
  33. 33.
    Seckinger P, Lowenthal JW, Williamson K, Dayer JM, McDonald MR (1987) A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol 139:1546–1549Google Scholar
  34. 34.
    Symons JA, Eastgate JA, Duff GW (1989) Identification of a specific IL1-binding protein in serum, synovial cells and joint fluids from rheumatic patients. Br J Rheumatol (in press)Google Scholar
  35. 35.
    Di Giovine FS, Meager A, Leung M, Duff GW (1988) Immunoreactive tumour necrosis factor alpha and biological inhibitor(s) in synovial fluids from rheumatic patients. Int J Immunopathol Pharmacol 1:17–26Google Scholar
  36. 36.
    Endres S, Lonnemann G, Van der Meer JWM, Cannon JG, Ikejima T, Orencole S, Dinarello CA (1987) Use of a highly sensitive radioimmunoassay for measuring intraindividual variation of human monocyte interleukin 1 production. Immunobiology 175:48 (A4 abstr)Google Scholar
  37. 37.
    Rooney M, Symons JA, Duff GW (1989) Local interleukin 1 beta concentration correlates with local disease activity in rheumatoid arthritis. Br J Rheumatol (in press)Google Scholar
  38. 38.
    Eastgate JA, Symons JA, Wood NC, Grinlinton FM, di Giovine FS, Duff GW (1988) Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet II:706–709Google Scholar
  39. 39.
    Cannon JC, Van der Meer JWM, Kwiatkowski D, Endres S, Lonnemann G, Burke J, Dinarello CA (1988) Interleukin 1 beta in human plasma: optimization of blood collection, plasma extraction, and radioimmunoassay methods. Lymphokine Res 7:457–467Google Scholar
  40. 40.
    Di Giovine FS, Situnayake RD, Duff GW (1987) Radioimmunoassay of interleukin 1 beta in acute and chronic rheumatic diseases. Br J Rheumatol 26 (suppl 1):56Google Scholar
  41. 41.
    Di Giovine FS, Nuki G, Duff GW (1988) Tumour necrosis factor in synovial exudates. Ann Rheum Dis 47:768–772Google Scholar
  42. 42.
    Duff GW, Dickens E, Wood N, Manson J, Symons J, Poole S, di Giovine FS (1988) Immunoassays, bioassay and in situ hybridization of monokines in human arthritis. In: Powanda MC, Oppenheim JJ, Kluger MJ, Dinarello CA (eds) Monokines and other non-lymphocytic cytokines. Liss, New York, pp 387–392Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • F. S. di Giovine
    • 1
  • S. Poole
    • 2
  • R. D. Situnayake
    • 1
  • M. Wadhwa
    • 2
  • G. W. Duff
    • 1
  1. 1.Department of Medicine, Rheumatic Diseases UnitUniversity of Edinburgh, Northern General HospitalEdinburghUK
  2. 2.National Institute for Biological Standards and ControlPotters BarUK

Personalised recommendations