Abstract
Interleukin (IL)-10, an immunomodulatory cytokine predominantly produced by monocytes/macrophages and T cells, inhibits several functions of dendritic cells (DC), monocytes and T cells including their cytokine production, but it stimulates B cell immunoglobulin (Ig) production and cytotoxic T lymphocyte (CTL) generation. A precise knowledge of the mechanisms that control the IL-10 production is therefore highly important for understanding the immunoregulation. The IL-10 production was studied in cultures of freshly isolated human T cells. A rise in intracellular calcium as well as the common gamma-chain containing cytokine receptor triggering or CD28 triggering were found to be important signals for IL-10 induction. CD80, CD58, rIL-12 and rIFN-alpha all had efficacious and independent costimulatory activities on the IL-10 production, while PGE2 was inhibitory. Dependence on autocrine IL-2 signalling was shown by the effects of anti-IL-2 and anti-IL-2R monoclonal antibodies (MoAb), but the IL-10 production proceeded partly IL-2-independent when CD80 provided costimulation. Sensitivity to inhibition by CsA was not removed by CD80 or CD58 costimulation and/or by addition of rIL-12 or rIFN-alpha, pointing to the absolute requirement for calcineurin activity. These data reveal important differences in the regulatory pathways between IL-10 (a cytokine-inhibitory interleukin) and IL-2 (a cytokine-inducing interleukin), which can potentially be exploited therapeutically. The fact that CsA blocks the production of IL-10, which itself has important immunosuppressive properties, should be taken into account in defining immunosuppressive treatment schedules which include the use of CsA.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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B7-1 Antigen / physiology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism*
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CD58 Antigens / physiology
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Calcineurin / physiology
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Calcium Signaling
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Cells, Cultured / drug effects
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cyclosporine / pharmacology
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DNA-Binding Proteins / metabolism
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Dinoprostone / pharmacology
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Gene Expression Regulation* / drug effects
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Humans
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Immunosuppressive Agents / pharmacology
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Interferon Type I / pharmacology
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Interleukin-10 / biosynthesis*
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Interleukin-10 / genetics
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-12 / pharmacology
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / immunology
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Interleukin-2 / pharmacology
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Ionomycin / pharmacology
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Ionophores / pharmacology
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Leukocyte Common Antigens / analysis
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Lymphocyte Activation / drug effects
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NFATC Transcription Factors
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Nuclear Proteins*
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Protein Kinase C / metabolism
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Recombinant Proteins / pharmacology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / metabolism
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factors / metabolism
Substances
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Antibodies, Monoclonal
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B7-1 Antigen
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CD58 Antigens
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DNA-Binding Proteins
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Immunosuppressive Agents
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Interferon Type I
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Interleukin-2
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Ionophores
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NFATC Transcription Factors
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Nuclear Proteins
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Recombinant Proteins
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Transcription Factors
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Interleukin-10
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Interleukin-12
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Ionomycin
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Cyclosporine
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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Calcineurin
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Leukocyte Common Antigens
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Dinoprostone
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Tetradecanoylphorbol Acetate