Skip to main content
Log in

Interleukin-1 receptor antagonist inhibits calcium accumulation in in vivo chronic granuloma induced by potassium permanganate

  • Laboratory Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Summary

Interleukin-1 (IL-1) is a monokine that exerts multiple biological activity, including immunity and inflammation. Moreover, IL-1 is involved in Ca2+ release causing hypercalcemia and bone resorption. Recently, a 22 kDa natural inhibitor to IL-1 called interleukin-1 receptor antagonist (IL-1ra) has been described in human fluids, which specifically binds IL-1α or IL-1β receptors. In this study, we found that experimental granuloma induced by subcutaneous injections (0.2 ml) of potassium permanganate (KMnO4) 1:40 saturated crystal solution, after 7 days was strongly inhibited in size, weight and calcium content (measured as dry ash weight by incineration of granuloma tissue) compared with untreated controls, in mice treated intraperitoneally with IL-1ra (20 μg/bolus) given twice; the first at the same time of the induction of the granuloma and the second 24 hours later. In addition, leukotriene B4 and prostaglandin E2 were also inhibited in fresh granuloma of mice treated with IL-1ra. Taken together, these findings conclude for the first time, that the accumulation of calcium in chronic inflammatory states is strongly inhibited by IL-1ra, which decreases tissue calcergy and can potentially be useful for the treatment of calcium-related inflammatory diseases and malignancy-associated hypercalcemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Dinarello CA (1989) Interleukin-1 and its biologically related cytokine. Adv Immunol 44:153–205

    CAS  PubMed  Google Scholar 

  2. Neta R, Oppenheim JJ, Schrbeiber RD, Chizzonite R, Ledney GD, McVittie TJ (1991) Role of cytokines (interleukin-1 tumor necrosis factor, and transforming growth factor β) in natural and lipopolysaccharide-enhanced radioresistance. J Exp Med 173:1177–1182

    Article  CAS  PubMed  Google Scholar 

  3. Oppenheim JJ, Kovacs EJ, Matsushima K, Durham SK (1986) There is more than one interleukin-1. Immunol Today 7:45–56

    Article  CAS  Google Scholar 

  4. Ferreira SH, Lorenzetti BB, Bristow AF, Poole S (1988) Interleukin-1β as a potent hyperalgesis agent antagonized by a tripeptide analogue. Nature 334:698–700

    Article  CAS  PubMed  Google Scholar 

  5. Conti P (1991) Interleukin-1 and interleukin-1 receptor antagonist (IL-1ra). Ann Med Interne 142:521–525

    CAS  Google Scholar 

  6. Di Giovine FS, Malawista SE, Nuki G, Duff GW (1987) Interleukin-1 (IL-1) as a mediator of crystal arthritis. Stimulation of T cells and synovial fibroblast mitogenesis by urate crystal-induced IL-1. J Immunol 138:3213–3218

    PubMed  Google Scholar 

  7. Watrons DA, Andrews BS, Levonian PJ, Friou GJ (1990) Effect of human 17 kDa interleukin-1, 25–31 kDa thymocyte stimulating activity and the 6–9 kDa interleukin-1 inhibitor on calcium release in the newborn murine calvarial assay. J Rheumatol 17:1142–1147

    Google Scholar 

  8. Sato K (1988) A paraneoplastic syndrome of hypercalcemia and leukocytosis associated with solid tumors: production of interleukin 1 alpha (IL-lalpha) and granulocyte colony-stimulating factor (G-CSF) by clonal squamous cell carcinoma cells. Nippon Naiburpi Gakkai Zasshi 64:1223–1227

    CAS  Google Scholar 

  9. Matsuda T, Matsui K, Shimakoshi Y, Aida Y, Hukuda S (1991) 1-Hydroxyethylidene-1 1-bisphosphosphonate decreases the postovariectomy-enhanced interleukin-1 secretion from peritoneal macrophages in adult rats. Calcif Tissue Int 49:403–406

    CAS  PubMed  Google Scholar 

  10. Sacchettini G, Meucci O, Florio T, Scala G, Landolfi E, Grimaldi M (1988) Effect of interleukin-1 beta on transducing mechanisms in 325-1 clonal pituitary cells: part II. Modulation of calcium fluxes. Biochem Biophys Res Commun 155:1097–1104

    Google Scholar 

  11. Georgilis K, Schafer C, Dinarello CA, Klempner MS (1987) Human recombinant interleukin-1 beta has no effect on intracellular calcium or on functional responses on human neutrophils. J Immunol 138:3403–3407

    CAS  PubMed  Google Scholar 

  12. Seckinger P, Lowenthal JW, Williamson K, Dayer J-M, MacDonald HR (1987) A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol 139:1546–1549

    CAS  PubMed  Google Scholar 

  13. Hannum CH, Wilcox CJ, Arend WP, Joslin FP, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336–340

    Article  CAS  PubMed  Google Scholar 

  14. Jacobs C, Young D, Tyler S, Callis G, Gillis S, Conlou IJ (1988) In vivo treatment with IL-1 reduces the severity and duration of antigen-induced arthritis in rats. J Immunol 141:2967–2974

    CAS  PubMed  Google Scholar 

  15. Arend WP (1991) Interleukin-1 receptor antagonist: a new member of the interleukin-1 family. J Clin Invest 88:1445–1451

    CAS  PubMed  Google Scholar 

  16. Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonist. Blood 77:1627–1652

    CAS  PubMed  Google Scholar 

  17. Balavoine JF, de Rochemonteix B, Williamson K, Seckinger P, Cruchaud A, Dayer J-M (1986) Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by a urine-derived human interleukin-1 and inhibitor(s). J Clin Invest 78:1120–1124

    CAS  PubMed  Google Scholar 

  18. Seckinger P, Kleine-Nulend J, Alander C, Thompson RC, Dayer JM, Raisz LG (1990) Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production. J Immunol 145:4181–4184

    CAS  PubMed  Google Scholar 

  19. Selye H (1962) Calciphylaxis. University of Chicago Press, Chicago, USA, p 552

    Google Scholar 

  20. Selye H, Somogyi A, Mecs I (1986) Inhibition of local calcergy by topical application of calciphylactic challangers. Calcif Tissue Res 2:67–76

    Google Scholar 

  21. Gabbiani G, Jacqmin ML, Richard RM (1966) Soft-tissue calcification induced by rare earth metals and its prevention by sodium pyrophosphate. Br J Pharmacol 27:1–9

    CAS  Google Scholar 

  22. Lewis RA, Mencia-Huerta JM, Soberman RJ (1982) Radioimmunoassay for leukotriene B4. Proc Natl Acad Sci USA 79:7904–7908

    CAS  PubMed  Google Scholar 

  23. Zijlastra FJ, Vincent JE (1984) Determination of leukotriene and prostaglandins in [14C] arachidonic acid-labeled human lung tissue by high performance liquid chromatography and radioimmunoassay. J Chromat 311:39–44

    Google Scholar 

  24. Elliott GR, Van de Ment D (1991) Human recombinant interleukin-la enhances basal and arachidonic acid-stimulated synthesis of cyclooxygenase and lipoxygenase metabolites by human skin fibroblasts in vitro. Int J Immunopathol Pharmacol 4:67–74

    Google Scholar 

  25. Salmon JA, Simmons PM, Palmer RMJ (1982) A radioimmunoassay for leukotriene B4. Prostaglandins 12:929–941

    Google Scholar 

  26. Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA (1988) Interleukin-1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of a cyclooxygenase inhibitor. J Clin Invest 81:1162–1172

    CAS  PubMed  Google Scholar 

  27. Conti P, Cifone MG, Alesse E, Reale M, Fieschi C, Dinarello CA (1986) In vitro-enhanced thromboxane B2 release by polymorphonuclear leukocytes and macrophages after treatment with human recombinant interleukin-1. Prostaglandins 32:111–115

    Article  CAS  PubMed  Google Scholar 

  28. Conti P, Continenza MA (1980) Decreased ulcerogenic effect of indomethacin in the rat when given in association with diflunisal. J Pathol 131:357–361

    Article  CAS  PubMed  Google Scholar 

  29. Conti P, Reale M, Trisi P, Barbacane RC, Panara MR, Bongrazio M, Piattelli A (1990) Lipoxins increase granuloma formation induced by potassium permanganate in vivo. Agents Actions 29:50–51

    Article  CAS  PubMed  Google Scholar 

  30. Continenza MA, Conti P, Gigante GE (1980) Calcium content of experimental granuloma as determined by x-ray fluorescence. Influence of non-steroidal anti-inflammatory drugs. Experientia 36:230–231

    Article  CAS  PubMed  Google Scholar 

  31. Conti P, Dempsey RA, Reale M, Barbacane RC, Panara MR, Bongrazio M, Mier JW (1991) Activation of human natural killer cells by lipopolysaccharide and generation of interleukin-1α, β, tumor necrosis factor and interleukin-6. Effect of interleukin-1 receptor antagonist. Immunology 73:450–456

    CAS  PubMed  Google Scholar 

  32. Ulich TR, Yin S, Guo K, del Castillo J, Eisenberg SP, Thompson RC (1991) The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin and IL-1-induced acute inflammation. Am J Pathol 138:521–524

    CAS  PubMed  Google Scholar 

  33. Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA (1991) A specific receptor antagonist for IL-1 prevents Escherichia coli-induced shock in rabbits. FASEB J 5:338–343

    CAS  PubMed  Google Scholar 

  34. Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP (1991) Interleukin-1 (IL-1) receptor antagonist binds to a 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266:10331–10336

    CAS  PubMed  Google Scholar 

  35. Sabatini M, Boyce B, Aufdemorte T, Bonewald L, Mundy GR (1988) Infusion of recombinant human interleukin-1 alpha and beta causes hypercalcemia in normal mice. Proc Natl Acad Sci USA 85:5235–5239

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Conti, P., Reale, M., Panara, M.R. et al. Interleukin-1 receptor antagonist inhibits calcium accumulation in in vivo chronic granuloma induced by potassium permanganate. Calcif Tissue Int 52, 300–304 (1993). https://doi.org/10.1007/BF00296655

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00296655

Key words

Navigation