Inflammation Research

, Volume 59, Issue 3, pp 189–196 | Cite as

Diacerein decreases TNF-α and IL-1β levels in peritoneal fluid and prevents Baker’s yeast-induced fever in young rats

  • Juliana Saibt Martins Pasin
  • Ana Paula Oliveira Ferreira
  • André Luis Lopes Saraiva
  • Viviane Ratzlaff
  • Rosália Andrighetto
  • Jorgete Tomazetti
  • Daiana Silva Ávila
  • Sydney Hartz Alves
  • Maribel Antonello Rubin
  • Juliano Ferreira
  • Adair Roberto Soares Santos
  • Carlos Fernando MelloEmail author
Original Research Paper



To investigate the effect of diacerein, an anti-inflammatory drug, on body temperature and protocols of fever induction in male Wistar rats.


The effect of diacerein (5.0 mg/kg, s.c.) on rectal temperature (T R) changes induced by Baker’s yeast (0.135 g/kg, i.p.) and PGE2 (10 ng/animal, i.t.) was evaluated. T R changes were recorded over time. The leukocyte count and TNF-α and IL-1β content were evaluated in the peritoneal fluid by means of optical microscopy and enzyme immunoassay (ELISA kits), respectively.


The administration of diacerein to febrile animals attenuated Baker’s yeast-induced fever but did not alter prostaglandin E2-induced fever. Diacerein prevented the development of Baker’s yeast-induced fever and significantly attenuated the increase in peritoneal leukocytes and decreased IL-1β and TNF-α levels in peritoneal fluid.


These data suggest that diacerein partially protects against Baker’s yeast-induced fever and peritoneal leukocyte migration, and indicate that this effect appears to be due to inhibition of release of cytokines (such as TNF-α and IL-1β).


Fever Cytokines Leukocyte migration In vivo inflammation Infection Baker’s yeast 



The authors thank Paulino Aguiar and Florindo Duarte for competent technical support. Research supported by CNPq, CAPES and FAPERGS. C.F.M. and M.A.R. are the recipients of CNPq fellowships, grant numbers 500120/2003-0 and 500096/2003-1, respectively.


  1. 1.
    Zeisberger E. From humoral fever to neuroimmunological control of fever. J Therm Biol. 1999;24:287–326.CrossRefGoogle Scholar
  2. 2.
    Szelényi J. Cytokines and the central nervous system. Brain Res Bull. 2000;54:329–38.CrossRefGoogle Scholar
  3. 3.
    Kluger MJ. Fever: role of pyrogens and cryogens. Physiol Rev. 1991;71:93–127.PubMedGoogle Scholar
  4. 4.
    Kluger MJ, Kozak W, Leon LR, Conn CA. The use of knockout mice to understand the role of cytokines in fever. Clin Exp Pharmacol Physiol. 1998;25:141–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Dascombe MJ, Rotwell NJ, Sagay BO, Stock MJ. Pyrogenic and thermogenic effects of interleukin-1β in the rat. Am J Physiol. 1989;256:7–11.Google Scholar
  6. 6.
    Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, Van Der Meer JW, et al. Circulating interleukin-1 and tumour necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis. 1990;161:79–84.PubMedGoogle Scholar
  7. 7.
    Nakamori T, Morimoto A, Yamaguchi K, Watanabe T. Interleukin-1 beta production in the rabbit brain during endotoxin-induced fever. J Physiol. 1994;476:177–86.PubMedGoogle Scholar
  8. 8.
    Luheshi GN, Hammond E, Van Dam AM. Cytokines as messengers of neuroimmune interactions. Trends Neurosci. 1996;19:46–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Smith BK, Kluger MJ. Human IL-1 receptor antagonist partially suppresses LPS fever but not plasma levels of IL-6 in Fischer rats. Am J Physiol. 1992;263:653–5.Google Scholar
  10. 10.
    Kozak W, Kluger MJ, Soszynski D, Conn CA, Rudolph K, Leon LR, et al. IL-6 and IL-1[beta] in fever: studies using cytokine-deficient (knockout) mice. Ann N Y Acad Sci. 1998;856:33–47.CrossRefPubMedGoogle Scholar
  11. 11.
    Ataoglu H, Dogan MD, Mustafa F, Akarsu ES. Candida albicans and Saccharomyces cerevisiae cell wall mannans produce fever in rats. Role of nitric oxide and cytokines. Life Sci. 2000;67:2247–56.CrossRefPubMedGoogle Scholar
  12. 12.
    Holt SJ, Grimble RF, York DA. Tumour necrosis factor-α and lymphotoxin have opposite effects on sympathetic efferent nerves to brown adipose tissue by direct action in the central nervous system. Brain Res. 1989;497:183–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Moldovan F, Pelletier JP, Jolicoeur FC, Cloutier JM, Martel-Pelletier J. Diacerhein and rhein reduce the ICE-induced IL-1β and IL-18 activation in human osteoarthritic cartilage. Osteoarthr Cartil. 2000;8:186–96.CrossRefPubMedGoogle Scholar
  14. 14.
    Chantre P, Cappelarre A, Leblan D, Guedon D, Vandermander J, Fournie B. Efficacy and tolerance of Harpagophytum procumbens versus diacerhein in treatment of osteoarthritis. Phytomedicine. 2000;7:177–83.PubMedGoogle Scholar
  15. 15.
    Nicolas P, Tod M, Padoin C, Petitjean O. Clinical pharmacokinetics of diacerein. Clin Pharmacokinet. 1998;35:347–59.CrossRefPubMedGoogle Scholar
  16. 16.
    Moore AR, Greenslade KJ, Alam CAS, Willoughby DA. Effects of diacerhein on granuloma induced cartilage breakdown in the mouse. Osteoarthr Cartil. 1998;6:19–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Spencer CM, Wilde MI. Diacerein. Drugs. 1997;53:98–106.CrossRefPubMedGoogle Scholar
  18. 18.
    Pietrangelo A, Montosi G, Recalcati S, Garuti C, Cairo G. Diacerhein blocks iron regulatory protein activation inflamed human monocytes. Life Sci. 1998;63:213–9.CrossRefGoogle Scholar
  19. 19.
    Yaron M, Shirazi I, Yaron I. Effets anti-interleukin-1 de la diacerhéine in vitro. Rev Prat. 1997;47:20–3.Google Scholar
  20. 20.
    Tomazzeti J, Ávila DS, Ferreira APO, Martins JS, Souza FR, Royer C, et al. Baker’s yeast-induced fever in young rats: characterization and validation of an animal model for antipyretics screening. J Neurosci Methods. 2005;147:29–35.CrossRefGoogle Scholar
  21. 21.
    National Committee for Clinical and Laboratory Standards (NCCLS). Reference method for dilution antifungal susceptibility testing of yeasts: approved standard. Documents M27-A2. 2002; Villanova, PA. V.17. n.9.Google Scholar
  22. 22.
    Mestre C, Pélissier T, Fialip J, Wilcox G, Eschalier A. A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods. 1994;32:197–200.CrossRefPubMedGoogle Scholar
  23. 23.
    Quintão NLM, Medeiros R, Santos ARS, Campos MM, Calixto JB. The effects of diacerhein on mechanical allodynia in inflammatory and neuropathic models of nociception in mice. Anesth Analg. 2005;101:1763–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Tamura T, Shirai T, Kosaka N, Ohmori K, Takafumi N. Pharmacological studies of diacerein in animal models of inflammation, arthritis and bone resorption. Eur J Pharmacol. 2002;448:81–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Martel-Pelletier J, Mineau F, Jolicouer FC, Cloutier JM, Pelletier JP. In vitro effects of diacerhein and rhein on interleukin-1 and tumour necrosis factor-alpha systems in human osteoarthritic synovium and chondrocytes. J Rheumatol. 1998;25:756–62.Google Scholar
  26. 26.
    Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-Pelletier J. Diacerhein and rhein reduce the interleukin-1 beta stimulated inducible nitric oxide synthesis level and activity while stimulating cyclooxygenase-2 synthesis in human osteoarthritic chondrocytes. J Rheumatol. 1998;25:2417–24.PubMedGoogle Scholar
  27. 27.
    Yaron M, Shirazi I, Yaron I. Anti-interleukin-1 effects of diacerein and rhein in human osteoarthritic synovial tissue and cartilage cultures. Osteoarthr Cartil. 1999;7:272–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Ferreira-Mendes A, Caramona MM, Carvalho AP, Lopes MC. Diacerhein and rhein prevent interleukin-1β-induced nuclear factor-κb activation by inhibiting the degradation of inhibitor κB-α. Pharmacol Toxicol. 2002;91:22–8.CrossRefGoogle Scholar
  29. 29.
    Bonizzi G, Karin M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25:280–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Yoshida S, Kato T, Sakurada S, Kurono C, Yang JP, Matsui N, et al. Inhibition of IL-6 and IL-8 induction from cultured rheumatoid synovial fibroblasts by treatment with aurothioglucose. Int Immunol. 1999;11:151–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Hoffmann A, Levchenko A, Scott MI, Baltimore D. The IκB–NF-κB signaling module: temporal control and selective gene activation. Science. 2002;298:1241–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Ziegelbauer K, Gantner F, Lukacs NW, Berlin A, Fuchikami K, Niki T, et al. A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity. Br J Pharmacol. 2005;145:178–82.CrossRefPubMedGoogle Scholar
  33. 33.
    Saleh TS, Calixto JB, Medeiros YS. Effects of anti-inflammatory drugs upon nitrate and myeloperoxidase levels in the mouse pleurisy induced by carrageenan. Peptides. 1999;20:949–56.CrossRefPubMedGoogle Scholar
  34. 34.
    Mian M, Azzara A, Benetti D. Studies in vitro on the effects of rhein on the chemotaxis of human leukocytes. Int J Tissue React. 1987;9:459–63.PubMedGoogle Scholar
  35. 35.
    Morimoto A, Murakami N, Watanabe T. Dehydration enhances endotoxin fever by increased production of endogenous pyrogen. Am J Physiol. 1986;251:41–7.Google Scholar
  36. 36.
    Bevilacqua MP, Pober PS, Mendric DL, Cotran RS, Gimbrone NA. Identification of an inducible endothelial leukocyte adhesion molecule, ELAM-1. Proc Natl Acad Sci USA. 1987;84:9238–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Mantovani A, Dejana E. Cytokines as communication signals between leukocyte and endothelial cells. Immunol Today. 1989;10:370–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Bevilacqua MP, Nelson RM. Selectins. J Clin Invest. 1993;91:379–87.CrossRefPubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  • Juliana Saibt Martins Pasin
    • 1
  • Ana Paula Oliveira Ferreira
    • 1
  • André Luis Lopes Saraiva
    • 1
  • Viviane Ratzlaff
    • 1
  • Rosália Andrighetto
    • 1
  • Jorgete Tomazetti
    • 1
  • Daiana Silva Ávila
    • 1
  • Sydney Hartz Alves
    • 2
  • Maribel Antonello Rubin
    • 3
  • Juliano Ferreira
    • 3
  • Adair Roberto Soares Santos
    • 4
  • Carlos Fernando Mello
    • 1
    Email author
  1. 1.Department of PhysiologyUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Department of Microbiology and Parasitology, Center of Health SciencesUniversidade Federal de Santa MariaSanta MariaBrazil
  3. 3.Department of Chemistry, Center of Exact and Natural SciencesUniversidade Federal de Santa MariaSanta MariaBrazil
  4. 4.Department of Physiological SciencesUniversidade Federal de Santa CatarinaFlorianópolisBrazil

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