Enhancement of endotoxin-induced interleukin-10 production by SR 31747A, a sigma ligand.
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.
Bourrie
B
B
Sanofi Recherche, Department of Immunopharmacology, Montpellier, France.
Bouaboula
M
M
Benoit
J M
JM
Derocq
J M
JM
Esclangon
M
M
Le Fur
G
G
Casellas
P
P
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001483:Base Sequence; D003510:Cyclohexanes / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology / Q000633:toxicity; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017480:Receptors, sigma / Q000819:agonists*; D012772:Shock, Septic / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003510:Cyclohexanes; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017480:Receptors, sigma; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005688:Galactosamine; D003907:Dexamethasone; D007371:Interferon-gamma; D016572:Cyclosporine; C088447:SR 31747