Inhibition of p38 MAP kinase during cellular activation results in IFN-gamma-dependent augmentation of IL-12 production by human monocytes/macrophages

J B Marriott, I A Clarke, A G Dalgleish

    Research output: Contribution to journalArticle

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    Abstract

    Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antigen-presenting cells that promotes cellular immunity and enables the generation of protective immunity against intracellular pathogens and tumours. Therefore, modulation of IL-12 activity is a primary immunotherapeutic goal. However, little is known about its regulation. Signalling via p38 MAPK has been implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK inhibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS induced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-independent and T cell-dependent stimuli but not in unstimulated cultures, indicating that activation signals are required. Furthermore, the production of IFN-gamma by T cells is crucial as production was not increased in LPS-stimulated, purified adherent monocytes/macrophages without the addition of exogenous IFN-gamma. These results provide evidence that p38 MAPK has an unexpected suppressive effect on IL-12p40 gene transcription, and suggests interplay between p38 MAPK- and IFN-gamma -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of IL-12 as a key immunoregulatory cytokine suggests that the clinical application of pyrinidyl imidazole inhibitors, such as SB203580, may need to be reassessed.
    Original languageEnglish
    Pages (from-to)64-70
    Number of pages7
    JournalClinical and Experimental Immunology
    Volume125
    Issue number1
    Publication statusPublished - 2001

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    p38 Mitogen-Activated Protein Kinases
    Interleukin-12
    Monocytes
    Macrophages
    Interleukin-12 Subunit p40
    T-Lymphocytes
    Cytokines
    Antigen-Presenting Cells
    Cellular Immunity
    Immunity
    Messenger RNA
    Genes
    SB 203580
    Neoplasms
    Proteins

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    Inhibition of p38 MAP kinase during cellular activation results in IFN-gamma-dependent augmentation of IL-12 production by human monocytes/macrophages. / Marriott, J B; Clarke, I A; Dalgleish, A G.

    In: Clinical and Experimental Immunology, Vol. 125, No. 1, 2001, p. 64-70.

    Research output: Contribution to journalArticle

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    abstract = "Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antigen-presenting cells that promotes cellular immunity and enables the generation of protective immunity against intracellular pathogens and tumours. Therefore, modulation of IL-12 activity is a primary immunotherapeutic goal. However, little is known about its regulation. Signalling via p38 MAPK has been implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK inhibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS induced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-independent and T cell-dependent stimuli but not in unstimulated cultures, indicating that activation signals are required. Furthermore, the production of IFN-gamma by T cells is crucial as production was not increased in LPS-stimulated, purified adherent monocytes/macrophages without the addition of exogenous IFN-gamma. These results provide evidence that p38 MAPK has an unexpected suppressive effect on IL-12p40 gene transcription, and suggests interplay between p38 MAPK- and IFN-gamma -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of IL-12 as a key immunoregulatory cytokine suggests that the clinical application of pyrinidyl imidazole inhibitors, such as SB203580, may need to be reassessed.",
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