Enhancement of endotoxin‐induced interleukin‐10 production by SR 31747A, a sigma ligand

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.

Methylprednisolone differentially regulates IL-10 and tumour necrosis factor (TNF) production during murine endotoxaemia

“…Experiments conducted in vitro indicated that MPDS increases biosynthesis of IL-10 by LPSactivated peritoneal macrophages. As severe combined immunodeficient (SCID) mice challenged with LPS produce normal amounts of IL-10 [20], the increased levels of IL-10 induced by LPS in vivo are probably dependent on an increased IL-10 biosynthesis by macrophages. Several recent studies demonstrated that other molecules also differentially regulate the production of IL-10 and TNF induced by LPS.…”

“…Several recent studies demonstrated that other molecules also differentially regulate the production of IL-10 and TNF induced by LPS. These molecules include agents increasing cytoplasmic cAMP levels [25][26][27], chlorpromazine [30], a sigma-ligand [20], desferrioxamine and transforming growth factor-beta (TGF-) [31]. In the case of GCs, the enhancing effect on IL-10 production was also recently observed on macrophages stimulated in vitro with bacille Calmette-Guérin (BCG) (L. Sigola and G. J. Bancroft, personal communication).…”

“…As macrophages probably represent an important source of IL-10 during experimental endotoxaemia [20][21][22], we evaluated whether the differential regulation of TNF and IL-10 observed in vivo also occurs at the level of macrophages in vitro. We first studied the effects of MPDS on the production of IL-10 by LPS-activated mouse peritoneal cells.…”

“…Monocytes and macrophages represent probably an important source of IL-10 in inflammatory disorders [20][21][22]. The mechanisms controlling IL-10 production by monocytes/macrophages remain poorly understood.…”

Purification and Characterization of the Human SR 31747A-binding Protein

“…ies suffered from a lack of information on the binding protein involved to relate the observed effects to a biochemical process (36). In an attempt to decipher this, we have purified, cloned, sequenced, and expressed the SR-BP.…”