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. 1995 Dec;102(3):635–641. doi: 10.1111/j.1365-2249.1995.tb03864.x

The influence of tetracyclines on T cell activation.

M Kloppenburg 1, C L Verweij 1, A M Miltenburg 1, A J Verhoeven 1, M R Daha 1, B A Dijkmans 1, F C Breedveld 1
PMCID: PMC1553388  PMID: 8536384

Abstract

Minocycline has been shown to have an anti-inflammatory effect in patients with rheumatoid arthritis (RA). Since there is evidence that RA is a T cell-mediated disease, we investigated the effect of minocycline on human T cell clones derived from the synovium of an RA patient. The T cells, when activated via the T cell receptor (TCR)/CD3 complex, were suppressed functionally by minocycline, resulting in a dose-dependent inhibition of T cell proliferation and reduction in production of IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). Besides an inhibition of IL-2 production, minocycline exerted its effect on T cell proliferation by induction of a decreased IL-2 responsiveness. We showed that the chelating capacity of minocycline plays a crucial role in the inhibitory effect on T cell function, since the inhibitory effect on T cell proliferation could be annulled by addition of exogenous Ca2+. However, minocycline did not markedly influence the typical TCR/CD3-induced intracellular Ca2+ mobilization. Taken together, the results clearly indicate that minocycline has immunomodulating effects on human T cells.

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Selected References

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  1. ALBERT A., REES C. W. Avidity of the tetracyclines for the cations of metals. Nature. 1956 Mar 3;177(4505):433–434. doi: 10.1038/177433a0. [DOI] [PubMed] [Google Scholar]
  2. Banck G., Forsgren A. Antibiotics and suppression of lymphocyte function in vitro. Antimicrob Agents Chemother. 1979 Nov;16(5):554–560. doi: 10.1128/aac.16.5.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bax C. M., Shankar V. S., Towhidul Alam A. S., Bax B. E., Moonga B. S., Huang C. L., Zaidi M., Rifkin B. R. Tetracyclines modulate cytosolic Ca2+ responses in the osteoclast associated with "Ca2+ receptor" activation. Biosci Rep. 1993 Jun;13(3):169–174. doi: 10.1007/BF01149961. [DOI] [PubMed] [Google Scholar]
  4. Bellahsene A., Forsgren A. Effect of doxycycline on immune response in mice. Infect Immun. 1985 May;48(2):556–559. doi: 10.1128/iai.48.2.556-559.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bijsterbosch M. K., Rigley K. P., Klaus G. G. Cross-linking of surface immunoglobulin on B lymphocytes induces both intracellular Ca2+ release and Ca2+ influx: analysis with indo-1. Biochem Biophys Res Commun. 1986 May 29;137(1):500–506. doi: 10.1016/0006-291x(86)91238-6. [DOI] [PubMed] [Google Scholar]
  6. Crabtree G. R. Contingent genetic regulatory events in T lymphocyte activation. Science. 1989 Jan 20;243(4889):355–361. doi: 10.1126/science.2783497. [DOI] [PubMed] [Google Scholar]
  7. Gabler W. L., Creamer H. R. Suppression of human neutrophil functions by tetracyclines. J Periodontal Res. 1991 Jan;26(1):52–58. doi: 10.1111/j.1600-0765.1991.tb01626.x. [DOI] [PubMed] [Google Scholar]
  8. Gabler W. L. Fluxes and accumulation of tetracyclines by human blood cells. Res Commun Chem Pathol Pharmacol. 1991 Apr;72(1):39–51. [PubMed] [Google Scholar]
  9. Golub L. M., Lee H. M., Lehrer G., Nemiroff A., McNamara T. F., Kaplan R., Ramamurthy N. S. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res. 1983 Sep;18(5):516–526. doi: 10.1111/j.1600-0765.1983.tb00388.x. [DOI] [PubMed] [Google Scholar]
  10. Goodhart G. L. Further evidence for the role of bivalent cations in human polymorphonuclear leukocyte locomotion: recovery from tetracycline-induced inhibition in the presence of cation ionophores. J Reticuloendothel Soc. 1979 May;25(5):545–554. [PubMed] [Google Scholar]
  11. Greenwald R. A., Golub L. M., Lavietes B., Ramamurthy N. S., Gruber B., Laskin R. S., McNamara T. F. Tetracyclines inhibit human synovial collagenase in vivo and in vitro. J Rheumatol. 1987 Feb;14(1):28–32. [PubMed] [Google Scholar]
  12. Greenwald R. A., Moak S. A., Ramamurthy N. S., Golub L. M. Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. J Rheumatol. 1992 Jun;19(6):927–938. [PubMed] [Google Scholar]
  13. Gruters R. A., Otto S. A., Al B. J., Verhoeven A. J., Verweij C. L., Van Lier R. A., Miedema F. Non-mitogenic T cell activation signals are sufficient for induction of human immunodeficiency virus transcription. Eur J Immunol. 1991 Jan;21(1):167–172. doi: 10.1002/eji.1830210125. [DOI] [PubMed] [Google Scholar]
  14. Ingham E. Modulation of the proliferative response of murine thymocytes stimulated by IL-1, and enhancement of IL-1 beta secretion from mononuclear phagocytes by tetracyclines. J Antimicrob Chemother. 1990 Jul;26(1):61–70. doi: 10.1093/jac/26.1.61. [DOI] [PubMed] [Google Scholar]
  15. Ingham E., Turnbull L., Kearney J. N. The effects of minocycline and tetracycline on the mitotic response of human peripheral blood-lymphocytes. J Antimicrob Chemother. 1991 May;27(5):607–617. doi: 10.1093/jac/27.5.607. [DOI] [PubMed] [Google Scholar]
  16. KOHN K. W. Mediation of divalent metal ions in the binding of tetracycline to macromolecules. Nature. 1961 Sep 16;191:1156–1158. doi: 10.1038/1911156a0. [DOI] [PubMed] [Google Scholar]
  17. Kloppenburg M., Breedveld F. C., Terwiel J. P., Mallee C., Dijkmans B. A. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum. 1994 May;37(5):629–636. doi: 10.1002/art.1780370505. [DOI] [PubMed] [Google Scholar]
  18. Koenderman L., Yazdanbakhsh M., Roos D., Verhoeven A. J. Dual mechanisms in priming of the chemoattractant-induced respiratory burst in human granulocytes. A Ca2+-dependent and a Ca2+-independent route. J Immunol. 1989 Jan 15;142(2):623–628. [PubMed] [Google Scholar]
  19. Langevitz P., Bank I., Zemer D., Book M., Pras M. Treatment of resistant rheumatoid arthritis with minocycline: an open study. J Rheumatol. 1992 Oct;19(10):1502–1504. [PubMed] [Google Scholar]
  20. Macdonald H., Kelly R. G., Allen E. S., Noble J. F., Kanegis L. A. Pharmacokinetic studies on minocycline in man. Clin Pharmacol Ther. 1973 Sep-Oct;14(5):852–861. doi: 10.1002/cpt1973145852. [DOI] [PubMed] [Google Scholar]
  21. Martin R. R., Warr G. A., Couch R. B., Yeager H., Knight V. Effects of tetracycline on leukotaxis. J Infect Dis. 1974 Feb;129(2):110–116. doi: 10.1093/infdis/129.2.110. [DOI] [PubMed] [Google Scholar]
  22. Miltenburg A. M., van Laar J. M., de Kuiper R., Daha M. R., Breedveld F. C. T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol. 1992 May;35(5):603–610. doi: 10.1111/j.1365-3083.1992.tb03260.x. [DOI] [PubMed] [Google Scholar]
  23. Panayi G. S., Lanchbury J. S., Kingsley G. H. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 1992 Jul;35(7):729–735. doi: 10.1002/art.1780350702. [DOI] [PubMed] [Google Scholar]
  24. Park J. K., Dow R. C. The uptake and localization of tetracycline in human blood cells. Br J Exp Pathol. 1970 Apr;51(2):179–182. [PMC free article] [PubMed] [Google Scholar]
  25. Pepper G. M., Maimon J., Schneider B. S. Quantification and characterization of ACTH-related peptides produced by human peripheral blood mononuclear cells. Lymphokine Cytokine Res. 1991 Apr;10(1-2):133–140. [PubMed] [Google Scholar]
  26. Potts R. C., Hassan H. A., Brown R. A., MacConnachie A., Gibbs J. H., Robertson A. J., Beck J. S. In vitro effects of doxycycline and tetracycline on mitogen stimulated lymphocyte growth. Clin Exp Immunol. 1983 Aug;53(2):458–464. [PMC free article] [PubMed] [Google Scholar]
  27. Pruzanski W., Greenwald R. A., Street I. P., Laliberte F., Stefanski E., Vadas P. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol. 1992 Sep 25;44(6):1165–1170. doi: 10.1016/0006-2952(92)90381-r. [DOI] [PubMed] [Google Scholar]
  28. Rijkers G. T., Van Oosterom R., Van Muiswinkel W. B. The immune system of cyprinid fish. Oxytetracycline and the regulation of humoral immunity in carp (Cyprinus carpio). Vet Immunol Immunopathol. 1981 Jun;2(3):281–290. doi: 10.1016/0165-2427(81)90029-5. [DOI] [PubMed] [Google Scholar]
  29. Saivin S., Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet. 1988 Dec;15(6):355–366. doi: 10.2165/00003088-198815060-00001. [DOI] [PubMed] [Google Scholar]
  30. Thong Y. H., Ferrante A. Effect of tetracycline treatment on immunological responses in mice. Clin Exp Immunol. 1980 Mar;39(3):728–732. [PMC free article] [PubMed] [Google Scholar]
  31. Thong Y. H., Ferrante A. Inhibition of mitogen-induced human lymphocyte proliferative responses by tetracycline analogues. Clin Exp Immunol. 1979 Mar;35(3):443–446. [PMC free article] [PubMed] [Google Scholar]
  32. Tsien R. Y., Pozzan T., Rink T. J. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature. 1982 Jan 7;295(5844):68–71. doi: 10.1038/295068a0. [DOI] [PubMed] [Google Scholar]
  33. Van den Bogert C., Kroon A. M. Effects of oxytetracycline on in vivo proliferation and differentiation of erythroid and lymphoid cells in the rat. Clin Exp Immunol. 1982 Nov;50(2):327–335. [PMC free article] [PubMed] [Google Scholar]
  34. Van der Meide P. H., Dubbeld M., Schellekens H. Monoclonal antibodies to human immune interferon and their use in a sensitive solid-phase ELISA. J Immunol Methods. 1985 May 23;79(2):293–305. doi: 10.1016/0022-1759(85)90109-7. [DOI] [PubMed] [Google Scholar]
  35. Yu L. P., Jr, Smith G. N., Jr, Brandt K. D., Myers S. L., O'Connor B. L., Brandt D. A. Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum. 1992 Oct;35(10):1150–1159. doi: 10.1002/art.1780351007. [DOI] [PubMed] [Google Scholar]
  36. van Barr H. M., van de Kerkhof P. C., Mier P. D., Happle R. Tetracyclines are potent scavengers of the superoxide radical. Br J Dermatol. 1987 Jul;117(1):131–132. doi: 10.1111/j.1365-2133.1987.tb04104.x. [DOI] [PubMed] [Google Scholar]

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