Immunologic Research

, Volume 67, Issue 1, pp 84–92 | Cite as

Diminazene aceturate (Berenil) downregulates Trypanosoma congolense-induced proinflammatory cytokine production by altering phosphorylation of MAPK and STAT proteins

  • Shiby M. Kuriakose
  • Chukwunonso Onyilagha
  • Rani Singh
  • Ping Jia
  • Jude E. UzonnaEmail author
Original Article


Diminazene aceturate (Berenil) is the most commonly used trypanolytic agent in livestock. We previously showed that Berenil downregulates Trypanosoma congolense (T. congolense)-induced cytokine production in macrophages both in vitro and in vivo. Here, we investigated the molecular mechanisms through which the drug alters T. congolense-induced cytokine production in macrophages. We show that pretreatment of macrophages with Berenil significantly downregulated T. congolense-induced phosphorylation of mitogen-activated protein kinase (p38), signal transducer and activator of transcription (STAT) proteins including STAT1 and STAT3, and NFκB activity both in vitro and in vivo. Collectively, our results reveal a mechanistic insight through which Berenil downregulates T. congolense-induced cytokine production in macrophages by inhibiting key signaling molecules and pathways associated with proinflammatory cytokine production.


Diminazene aceturate (Berenil) Trypanosome Macrophages MAPK STAT1 Proinflammatory cytokines 


Compliance with ethical standards

The University of Manitoba Animal Care Committee approved all studies in accordance with the regulation of the Canadian Council on Animal Care.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Epidemiology and control of African Trypanosomiasis. Report of a WHO expert committee. World Health Organization. Geneva, Switzerland. Technical Report Series,. 1986 (Technical Report Series):No. 739.Google Scholar
  2. 2.
    Hursey BS. The programme against African trypanosomiasis: aims, objectives and achievements. Trends Parasitol. 2001;17(1):2–3.Google Scholar
  3. 3.
    Vincendeau P, Bouteille B. Immunology and immunopathology of African trypanosomiasis. An Acad Bras Cienc. 2006;78(4):645–65.Google Scholar
  4. 4.
    Dempsey WL, Mansfield JM. Lymphocyte function in experimental African trypanosomiasis. V. Role of antibody and the mononuclear phagocyte system in variant-specific immunity. J Immunol. 1983;130(1):405–11.Google Scholar
  5. 5.
    Shi M, Wei G, Pan W, Tabel H. Trypanosoma congolense infections: antibody-mediated phagocytosis by Kupffer cells. J Leukoc Biol. 2004;76(2):399–405.Google Scholar
  6. 6.
    Clayton CE, Selkirk ME, Corsini CA, Ogilvie BM, Askonas BA. Murine trypanosomiasis: cellular proliferation and functional depletion in the blood, peritoneum, and spleen related to changes in bone marrow stem cells. Infect Immun. 1980;28(3):824–31.Google Scholar
  7. 7.
    Grosskinsky CM, Ezekowitz RA, Berton G, Gordon S, Askonas BA. Macrophage activation in murine African trypanosomiasis. Infect Immun. 1983;39(3):1080–6.Google Scholar
  8. 8.
    Paulnock DM, Coller SP. Analysis of macrophage activation in African trypanosomiasis. J Leukoc Biol. 2001;69(5):685–90.Google Scholar
  9. 9.
    Schleifer KW, Mansfield JM. Suppressor macrophages in African trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins. J Immunol. 1993;151(10):5492–503.Google Scholar
  10. 10.
    Pan W, Ogunremi O, Wei G, Shi M, Tabel H. CR3 (CD11b/CD18) is the major macrophage receptor for IgM antibody-mediated phagocytosis of African trypanosomes: diverse effect on subsequent synthesis of tumor necrosis factor alpha and nitric oxide. Microbes Infect. 2006;8(5):1209–18.Google Scholar
  11. 11.
    Shi M, Wei G, Pan W, Tabel H. Experimental African trypanosomiasis: a subset of pathogenic, IFN-gamma-producing, MHC class II-restricted CD4+ T cells mediates early mortality in highly susceptible mice. J Immunol. 2006;176(3):1724–32.Google Scholar
  12. 12.
    Shi M, Pan W, Tabel H. Experimental African trypanosomiasis: IFN-gamma mediates early mortality. Eur J Immunol. 2003;33(1):108–18.Google Scholar
  13. 13.
    Uzonna JE, Kaushik RS, Gordon JR, Tabel H. Cytokines and antibody responses during Trypanosoma congolense infections in two inbred mouse strains that differ in resistance. Parasite Immunol. 1999;21(2):57–71.Google Scholar
  14. 14.
    Hertz CJ, Filutowicz H, Mansfield JM. Resistance to the African trypanosomes is IFN-gamma dependent. J Immunol. 1998;161(12):6775–83.Google Scholar
  15. 15.
    Kuriakose S, Muleme HM, Onyilagha C, Singh R, Jia P, Uzonna JE. Diminazene aceturate (Berenil) modulates the host cellular and inflammatory responses to Trypanosoma congolense infection. PLoS One. 2012;7(11):e48696.Google Scholar
  16. 16.
    Kuriakose S, Muleme H, Onyilagha C, Okeke E, Uzonna JE. Diminazene aceturate (Berenil) modulates LPS induced pro-inflammatory cytokine production by inhibiting phosphorylation of MAPKs and STAT proteins. Innate Immun. 2014;20(7):760–73.Google Scholar
  17. 17.
    Tabel H. Activation of the alternative pathway of bovine complement by Trypanosoma congolense. Parasite Immunol. 1982;4(5):329–35.Google Scholar
  18. 18.
    Lanham SM, Godfrey DG. Isolation of salivarian trypanosomes from man and other mammals using DEAE-cellulose. Exp Parasitol. 1970;28(3):521–34.Google Scholar
  19. 19.
    Biragyn A, Nedospasov SA. Lipopolysaccharide-induced expression of TNF-alpha gene in the macrophage cell line ANA-1 is regulated at the level of transcription processivity. J Immunol. 1995;155(2):674–83.Google Scholar
  20. 20.
    Fortier AH, Falk LA. Isolation of murine macrophages. Curr Protoc Immunol. 2001;Chapter 14:Unit 14 1.Google Scholar
  21. 21.
    Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. Curr Protoc Immunol. 2008;Chapter 14:Unit 14 1.Google Scholar
  22. 22.
    Wang JX, Hou LF, Yang Y, Tang W, Li Y, Zuo JP. SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-kappaB pathways in RAW 264.7 macrophages. Acta Pharmacol Sin. 2009;30(10):1428–35.Google Scholar
  23. 23.
    Huang H, Petkova SB, Pestell RG, Bouzahzah B, Chan J, Magazine H, et al. Trypanosoma cruzi infection (Chagas’ disease) of mice causes activation of the mitogen-activated protein kinase cascade and expression of endothelin-1 in the myocardium. J Cardiovasc Pharmacol. 2000;36(5 Suppl 1):S148–50.Google Scholar
  24. 24.
    Valere A, Garnotel R, Villena I, Guenounou M, Pinon JM, Aubert D. Activation of the cellular mitogen-activated protein kinase pathways ERK, P38 and JNK during Toxoplasma gondii invasion. Parasite. 2003;10(1):59–64.Google Scholar
  25. 25.
    Makela SM, Strengell M, Pietila TE, Osterlund P, Julkunen I. Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells. J Leukoc Biol. 2009;85(4):664–72.Google Scholar
  26. 26.
    Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.Google Scholar
  27. 27.
    Rao KM. MAP kinase activation in macrophages. J Leukoc Biol. 2001;69(1):3–10.Google Scholar
  28. 28.
    Campos MA, Almeida IC, Takeuchi O, Akira S, Valente EP, Procopio DO, et al. Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J Immunol. 2001;167(1):416–23.Google Scholar
  29. 29.
    Camargo MM, Almeida IC, Pereira ME, Ferguson MA, Travassos LR, Gazzinelli RT. Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes initiate the synthesis of proinflammatory cytokines by macrophages. J Immunol. 1997;158(12):5890–901.Google Scholar
  30. 30.
    Campos MA, Closel M, Valente EP, Cardoso JE, Akira S, Alvarez-Leite JI, et al. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol. 2004;172(3):1711–8.Google Scholar
  31. 31.
    Paulnock DM, Freeman BE, Mansfield JM. Modulation of innate immunity by African trypanosomes. Parasitology. 2010;137(14):2051–63.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Shiby M. Kuriakose
    • 1
  • Chukwunonso Onyilagha
    • 1
  • Rani Singh
    • 1
  • Ping Jia
    • 1
  • Jude E. Uzonna
    • 1
    Email author
  1. 1.Parasite Vaccines Development Laboratory, Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health SciencesUniversity of ManitobaWinnipegCanada

Personalised recommendations