Summary
Two types of tumor necrosis factor receptors have been characterized, both capable of transmitting the signal and exerting the biological functions of TNF and lymphotoxin. We measured the plasma concentrations of two types of TNF binding proteins (sTNFR-A and sTNFR-B) in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA) using an enzyme-linked binding assay. In normal controls (n = 43), mean plasma concentrations were 1030 ± 55 and 1461 ±59 pg/ml for sTNFR types A and B, respectively. In 67 patients with moderate RA, mean levels were 1422 ± 82 pg/ml (type A) and 2088 ± 109 pg/ml (type B); in 34 patients with severe RA, 2588 ±279 pg/ml and 4494 ± 550 pg/ml, respectively, were measured (P < 0.0001 compared to normal controls). Concentrations of both type A and type B sTNFR were highly correlated in severe RA (R2 = 0.7) but not in SpA or normal controls. T lymphocytes in synovial fluid of patients with RA expressed predominantly type A TNF receptors on their surface; in some patients a weaker expression of type B receptors was also detectable. Soluble TNF binding proteins in patients with RA were able to neutralize TNF in a cytotoxiity assay, demonstrating their ability to act as “TNF-inhibiting factors”. We conclude that both types of TNF receptors are parameters of disease activity in RA and may also act as TNF antagonists.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- TNF:
-
tumor necrosis factor
- TNFR:
-
tumor necrosis factor receptor
- sTNFR:
-
soluble tumor necrosis factor receptor
- RA:
-
rheumatoid arthritis
- SpA:
-
Spondylarthropathy
- ELIBA:
-
Enzyme linked binding assay
- mAb:
-
monoclonal antibody
References
Aggarwal BB, Essalu TE, Hass PE (1985) Characterization of receptors for human tumor necrosis factor and their regulation by γ interferon. Nature 318:665–668
Brockhaus M, Schoenfeld HJ, Schlaeger EJ, Hunziker W, Lesslauer W, Loetscher H (1990) Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci USA 87:3127–3132
Dembic Z, Loetscher H, Gubler U, Pan Y, Lahm H, Gentz R, Brockhaus M, Lesslauer W (1990) Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine 2:231–237
Digel W, Porzsolt F, Lesslauer W, Brockhaus M (1992) Evidence for soluble receptors for tumor necrosis factor in the serum of cancer patients — high levels in B-cell malignancies (in press)
Engelmann H, Aderka D, Rubinstein M, Rotman D, Wallach D (1989) A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity. J Biol Chem 264:11974–11980
Espevik T, Brockhaus M, Loetscher H, Nonstad U, Shalaby R (1990) Characterization of binding and biological effects of monoclonal antibodies against a human tumor necrosis factor receptor. J Exp Med 171:415–420
Gatanaga T, Hwang C, Kohr W, Cappuccini F, Lucci JA, Jeffes EWB, Lentz R, Tomich J, Yamamoto RS (1990) Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients. Proc Natl Acad Sci USA 87:8781–8784
Guerne PA, Zuraw BL, Vaughan JH, Carson DA, Lotz M (1989) Synovium as a source of interleukin 6 in vitro: contribution to local and systemic manifestations of arthritis. J Clin Invest 83:585–592
Heilig B, Mapara M, Brockhaus, Krauth K, Dörken B (1991) Two types of TNF-receptors are expressed on human normal and malignant B-lymphocytes. Clin Immunol Immunopathol 61:260–267
Henderson B, Pettipher ER (1987) Arthritogenic actions of recombinant IL 1 and TNF α in the rabbit: evidence for synergistic actions between cytokines in vivo. Clin Exp Immunol 75:306–310
Hirano T, Matsuda T, Turner M, Mijasaka N, Buchan G, Tand B, Sato K, Shimizu M, Maim R, Feldmann M, Kishimoto T (1988) Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18:1797–1801
Hohmann HP, Remy R, Brockhaus M, van Loon AP (1989) Two different cell types have different major receptors for human tumor necrosis factor (TNF alpha). J Biol Chem 264:14927–14933
Hopkins SJ, Meager A (1988) Cytokines in synovial fluid. II. The presence of tumour necrosis factor and interferon. Clin Exp Immunol 73:88–92
Husby G, Williams RC (1988) Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmunol 1:363–371
Loetscher HR, Pan YE, Lahm HW, Gentz R, Brockhaus M, Tabuchi H, Lesslauer W (1990) Molecular cloning and expression of the human 55 kD tumor necrosis factor receptor. Cell 61:351–357
Miossec P (1987) The role of interleukin 1 in the pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 5:305–308
Mosman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxic assays. J Immunol Methods 65:55–60
Old LJ (1985) Tumor necrosis factor (TNF). Science 230:630–632
Olson I, Lantz M, Nilsson E, Peetre C, Thyself H, Grubb A, Adolf G (1989) Isolation and characterization of a tumor necrosis factor binding protein from urine. Eur J Haematol 42:270–275
Porteu F, Nathan C (1990) Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med 172:599–607
Saxne T, Palladino MA, Heinegard D, Talal N, Wollheim FA (1988) Detection of tumor necrosis factor α but not tumor necrosis factor β in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31:1041–1045
Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong W, Gatanaga T, Granger GA, Lentz R, Raab H, Kohr WJ, Goeddel DV (1990) Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 61:361–367
Seckinger P, Isaaz S, Dayer JM (1989) Purification and characterization of a specific tumor necrosis factor alpha inhibitor. J Biol Chem 264:11966–11973
Sherry B, Cerami A (1988) Cachectin/tumor necrosis factor exerts endocrine, paracrine and autocrine control of inflammatory responses. J Cell Biol 107:1269–1275
Smith CA, Davis T, Anderson D, Solam L, Beckmann MP, Jerzy R, Dower SK, Cosman D, Goodwin RG (1990) A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 248:1019–1023
Spinas GA, Bloesch D, Kaufmann M, Keller U, Dayer J (1990) Induction of plasma inhibitors of interleukin 1 and TNFa by endotoxin administration to normal humans. J Clin Invest 990:R993–997
Urban JL, Shepard HM, Rothstein JL, Sugarman BJ, Schreiber H (1986) Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci USA 83:5233–5238
Yocum DE, Esparza L, Dubry S, Benjamin JB, Volz R, Scuderi P (1989) Characteristics of tumor necrosis factor production in rheumatoid arthritis. Cell Immunol 122:131–137
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Heilig, B., Wermann, M., Gallati, H. et al. Elevated TNF receptor plasma concentrations in patients with rheumatoid arthritis. Clin Investig 70, 22–27 (1992). https://doi.org/10.1007/BF00422933
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00422933