• 1.

    Chacon O, Bermudez LE, Barletta RG. Johne's disease, inflammatory bowel disease, and Mycobacterium paratuberculosis. Annu Rev Microbiol 2004;58:329363.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ryan P, Kelly RG & Lee G, et al. Bacterial DNA within granulomas of patients with Crohn's disease-detection by laser capture microdissection and PCR. Am J Gastroenterol 2001;99:15391543.

    • Search Google Scholar
    • Export Citation
  • 3.

    Perez V, Garcia Marin JF, Badiola JJ. Description and classification of different types of lesion associated with natural paratuberculosis infection in sheep. J Comp Pathol 1996;114:107122.

    • Search Google Scholar
    • Export Citation
  • 4.

    Khalifeh MS, Stabel JR. Effects of gamma interferon, interleukin-10, and transforming growth factor beta on the survival of Mycobacterium avium subsp. paratuberculosis in monocyte-derived macrophages from naturally infected cattle. Infect Immun 2004;72:19741982.

    • Search Google Scholar
    • Export Citation
  • 5.

    Khalifeh MS, Stabel JR. Upregulation of transforming growth factor-beta and interleukin-10 in cows with clinical Johne's disease. Vet Immunol Immunopathol 2004;99:3946.

    • Search Google Scholar
    • Export Citation
  • 6.

    Weiss DJ, Evanson OA, Souza CD. Increased expression of interleukin-10 and suppressor of cytokine signaling-3 associated with susceptibility to Johne's disease. Am J Vet Res 2005;66:11141120.

    • Search Google Scholar
    • Export Citation
  • 7.

    Weiss DJ, Evanson OA, Souza CD. Critical role of interleukin-10 in the response of bovine macrophages to infection by Mycobacterium avium sub paratuberculosis. Am J Vet Res 2005;66:721726.

    • Search Google Scholar
    • Export Citation
  • 8.

    Weiss DJ, Evanson OA & Moritz A, et al. Differential responses of bovine macrophages to Mycobacterium avium subsp. paratuberculosis and Mycobacterium avium subsp. avium. Infect Immun 2002;70:55565561.

    • Search Google Scholar
    • Export Citation
  • 9.

    Buza JJ, Hikono H & Mori Y, et al. Neutralization of interleukin-10 significantly enhances gamma interferon expression in peripheral blood by stimulation with Johnin purified protein derivative and by infection with Mycobacterium avium subsp. paratuberculosis in experimentally infected cattle with paratuberculosis. Infect Immun 2004;72:24252428.

    • Search Google Scholar
    • Export Citation
  • 10.

    Rao KM. MAP kinase activation in macrophages. J Leuko Biol 2001;69:1025.

  • 11.

    Reiling N, Blumenthal A & Flad HD, et al. Mycobacteria-induced TNF-alpha and IL-10 formation by human macrophages is differentially regulated at the level of mitogen-activated protein kinase activity. J Immunol 2001;15:33393345.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J 2000;14:21472157.

  • 13.

    Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001;81:807869.

    • Search Google Scholar
    • Export Citation
  • 14.

    Ferrer I, Blanco R & Carmona M, et al. Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. Acta Neuropathol 2002;103:391407.

    • Search Google Scholar
    • Export Citation
  • 15.

    Ferrer I, Blanco R, Carmona M. Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. Brain Res Mol Brain Res 2001;94:4858.

    • Search Google Scholar
    • Export Citation
  • 16.

    Buergelt CD, Williams JE. Nested PCR on blood and milk for the detection of Mycobacterium avium subsp paratuberculosis DNA in clinical and subclinical bovine paratuberculosis. Aust Vet J 2004;82:497503.

    • Search Google Scholar
    • Export Citation
  • 17.

    Stabel JR and Wagner BA, Relationships between fecal culture, ELISA, and bulk tank milk test results for Johne's disease in US dairy herds. J Dairy Sci 2002;85:525531.

    • Search Google Scholar
    • Export Citation
  • 18.

    Taddei S, Robbi C & Cesena C, et al. Detection of Mycobacterium avium subsp. paratuberculosis in bovine fecal samples: comparison of three polymerase chain reaction-based diagnostic tests with a conventional culture method. J Vet Diag Invest 2004;16:503508.

    • Search Google Scholar
    • Export Citation
  • 19.

    Arsic-Arsenijevic V, Dzamic A & Mitrovic S, et al. Characteristics of the immune response in protozoan infections. Med Pregl 2003;56:557563.

  • 20.

    Flynn JL, Chan J. Immune evasion by Mycobacterium tuberculosis: living with the enemy. Curr Opin Immunol 2003;15:450455.

  • 21.

    Oliveira MA, Santiago HC & Lisboa CR, et al. Leishmania sp: comparative study with Toxoplasma gondii and Trypanosoma cruzi in their ability to initialize IL-12 and IFN-gamma synthesis. Exp Parasitol 2000;95:96105.

    • Search Google Scholar
    • Export Citation
  • 22.

    Larsen L and Ropke C. Suppressors of cytokine signalling: SOCS. APMIS 2002;110:833844.

  • 23.

    Rouse J. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 1994;78:10271037.

    • Search Google Scholar
    • Export Citation
  • 24.

    Souza CD, Evanson OA, Weiss DJ. Mitogen activated protein kinase-p38 is an essential component in the interaction of Mycobacterium avium subsp. paratuberculosis with bovine monocytes. Microb Pathog 2006;Aug–Sep;41 (2–3):5966.

    • Search Google Scholar
    • Export Citation
  • 25.

    Haddad JJ, Saade NE, Safieh-Garabedian B. Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signaling modules targets for the anti-inflammatory action of this cytokine? Cell Signal 2003;15:255267.

    • Search Google Scholar
    • Export Citation
  • 26.

    Song CH, Lee JS & Lee SH, et al. Role of mitogen-activated protein kinase pathways in the production of tumor necrosis factor-alpha, interleukin-10, and monocyte chemotactic protein-1 by Mycobacterium tuberculosis H37Rv-infected human monocytes. J Clin Immunol 2003;23:194201.

    • Search Google Scholar
    • Export Citation
  • 27.

    Dao DN, Kremer L & Guerardel Y, et al. Mycobacterium tuberculosis lipomannan induces apoptosis and interleukin-12 production in macrophages. Infect Immun 2004;72:20672074.

    • Search Google Scholar
    • Export Citation
  • 28.

    Gollob JA, Veenstra KG & Jyonouchi H, et al. Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections. J Immunol 2000;165:41204126.

    • Search Google Scholar
    • Export Citation
  • 29.

    Kawakami K, Kinjo Y & Uezu K, et al. Interferon-gamma production and host protective response against Mycobacterium tuberculosis in mice lacking both IL-12p40 and IL-18. Microbes Infect 2004;6:339349.

    • Search Google Scholar
    • Export Citation
  • 30.

    Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Ann Rev Immunol 1995;13:251276.

    • Search Google Scholar
    • Export Citation
  • 31.

    Zatti RA, Chua J, Deretic V. Induction of p38 mitogen-activated protein kinase reduces early endosome autoantigen 1 (EEA1) recruitment to phagosomal membranes. J Biol Chem 2003;278:4696146967.

    • Search Google Scholar
    • Export Citation

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Regulation by Jun N-terminal kinase/stress activated protein kinase of cytokine expression in Mycobacterium avium subsp paratuberculosis–infected bovine monocytes

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  • 1 Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, 55018.
  • | 2 Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, 55018.
  • | 3 Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, 55018.

Abstract

Objective—To evaluate activation of Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway in bovine monocytes after incubation with Mycobacterium avium subsp paratuberculosis (Mptb) organisms.

Sample Population—Bovine monocytes obtained from 4 healthy adult Holstein dairy cows.

Procedures—Bovine monocytes were incubated with Mptb organisms with or without a specific inhibitor of the JNK/SAPK pathway (SP600125) for 2, 6, 24, or 72 hours. Expression of interleukin (IL)-1β, IL-10, IL-12, IL-18; transforming growth factor-β (TGF-β); and tumor necrosis factor-α (TNF-α) and the capacity of Mptb-infected monocytes to acidify phagosomes and kill Mptb organisms were evaluated. Phosphorylation status of JNK/SAPK was evaluated at 10, 30, and 60 minutes after Mptb incubation.

Results—Compared with uninfected control monocytes, Mptb-infected monocytes had increased expression of IL-10 at 2 and 6 hours after incubation and had increased expression of TNF-α, IL-1β, IL-18, and TGF-β at 2, 4, and 6 hours. Additionally, Mptb-infected monocytes had increased expression of IL-12 at 6 and 24 hours. Addition of SP600125 (specific chemical inhibitor of JNK/SAPK) resulted in a decrease in TNF-α expression at 2, 6, and 24 hours, compared with untreated Mptb-infected cells. Addition of SP600125 resulted in a decrease in TGF-β expression at 24 hours and an increase in IL-18 expression at 6 hours. Addition of SP600125 failed to alter phagosome acidification but did enhance the capacity of monocytes to kill Mptb organisms.

Conclusions and Clinical Relevance—Activation of JNK/SAPK may be an important mechanism used by Mptb to regulate cytokine expression in bovine monocytes for survival and to alter inflammatory and immune responses.

Abstract

Objective—To evaluate activation of Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway in bovine monocytes after incubation with Mycobacterium avium subsp paratuberculosis (Mptb) organisms.

Sample Population—Bovine monocytes obtained from 4 healthy adult Holstein dairy cows.

Procedures—Bovine monocytes were incubated with Mptb organisms with or without a specific inhibitor of the JNK/SAPK pathway (SP600125) for 2, 6, 24, or 72 hours. Expression of interleukin (IL)-1β, IL-10, IL-12, IL-18; transforming growth factor-β (TGF-β); and tumor necrosis factor-α (TNF-α) and the capacity of Mptb-infected monocytes to acidify phagosomes and kill Mptb organisms were evaluated. Phosphorylation status of JNK/SAPK was evaluated at 10, 30, and 60 minutes after Mptb incubation.

Results—Compared with uninfected control monocytes, Mptb-infected monocytes had increased expression of IL-10 at 2 and 6 hours after incubation and had increased expression of TNF-α, IL-1β, IL-18, and TGF-β at 2, 4, and 6 hours. Additionally, Mptb-infected monocytes had increased expression of IL-12 at 6 and 24 hours. Addition of SP600125 (specific chemical inhibitor of JNK/SAPK) resulted in a decrease in TNF-α expression at 2, 6, and 24 hours, compared with untreated Mptb-infected cells. Addition of SP600125 resulted in a decrease in TGF-β expression at 24 hours and an increase in IL-18 expression at 6 hours. Addition of SP600125 failed to alter phagosome acidification but did enhance the capacity of monocytes to kill Mptb organisms.

Conclusions and Clinical Relevance—Activation of JNK/SAPK may be an important mechanism used by Mptb to regulate cytokine expression in bovine monocytes for survival and to alter inflammatory and immune responses.

Contributor Notes

Supported in part by a grant from the University of Minnesota, Academic Health Center and USDA-NRI 2005-010447. Dr. Souza is a Research Fellow of the Coordenacao de Aperfeicoamento de Pessoal de Nível Superior, Brazil.

Address correspondence to Dr. Souza.