Abstract
SR 31747A is a new sigma ligand eliciting immunosuppressive and anti-inflammatory properties. Here, we show that SR 31747A greatly enhances lipopolysaccharide (LPS)-induced systemic release of interleukin (IL)-10, while it inhibits the secretion of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. In line with this finding, we also show by using quantitative reverse transcription-polymerase chain reaction analysis that SR 31747A increased LPS-induced IL-10 mRNA accumulation in spleen cells, whereas the level of both TNF-alpha and IFN-gamma mRNA was dramatically decreased. The enhancement of IL-10 production by SR 31747A treatment was also apparent in nude and severe-combined immunodeficient mice treated with LPS, clearly indicating that T and B cells were not involved. Finally, SR 31747A conferred protection against the lethal effect of LPS. The finding that SR 31747A strongly stimulates the synthesis of the natural anti-inflammatory cytokine IL-10, a property not observed with dexamethasone, provides new insights for the clinical use of this original compound, particularly in chronic inflammatory diseases where IL-10 is believed to be a pivotal regulatory component.
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Base Sequence
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Cyclohexanes / pharmacology*
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Cyclosporine / pharmacology
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DNA, Complementary / genetics
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Dexamethasone / pharmacology
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Female
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Galactosamine / toxicity
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Immunosuppressive Agents / pharmacology*
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-10 / biosynthesis*
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Interleukin-10 / genetics
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Interleukin-10 / metabolism
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Lipopolysaccharides / pharmacology
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Lipopolysaccharides / toxicity
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Lymphocyte Subsets / drug effects
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Lymphocyte Subsets / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mice, SCID
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Molecular Sequence Data
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Polymerase Chain Reaction
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, sigma / agonists*
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Shock, Septic / prevention & control
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclohexanes
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DNA, Complementary
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Immunosuppressive Agents
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Lipopolysaccharides
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RNA, Messenger
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Receptors, sigma
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Galactosamine
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Dexamethasone
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Interferon-gamma
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Cyclosporine
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SR 31747