SummaryBecause of its ability to efficiently inhibit in vitro cytokine production by activated macrophages, we hypothesized that interleukin (IL) 10 might be of particular interest in preventing endotoxininduced toxicity We therefore examined the effects of Ibl0 administration before lipopolysaccharide (LPS) challenge in mice. A marked reduction in the amounts of LPS-induced tumor necrosis factor (TNF) release in the circulation was observed after IL-10 pretreatment at doses as low as 10 U. Ibl0 also efficiently prevented the hypothermia generated by the injection of 100 #g LPS. Finally, pretreatment with a single injection of 1,000 U Ibl0 completely prevented the mortality consecutive to the challenge with 500 #g LPS, a dose that was lethal in 50% of the control mice. We conclude that Ibl0 inhibits in vivo TNF secretion and protects against the lethality of endotoxin in a murine model of septic shock.
Interleukin-10 (IL-10) is a potent inhibitor of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production and has been shown to protect mice from endotoxin shock. As IFN-gamma is another important mediator of LPS toxicity, we studied the effects of IL-10 on LPS-induced IFN-gamma synthesis in vitro and in vivo. First, we found that the addition of recombinant human IL-10 (rhIL-10) (10 U/ml) to human whole blood markedly suppressed LPS-induced IFN-gamma release while neutralization of endogenously synthesized IL-10 resulted in increased IFN-gamma levels. The ability of rIL-10 to inhibit LPS-induced IFN-gamma synthesis was also observed in vivo in mice. Indeed, administration of 1000 U recombinant mouse IL-10 (rmIL-10) 30 min before and 3 h after challenge of BALB/c mice with 100 micrograms LPS resulted in a threefold decrease in peak IFN-gamma serum levels. We then examined the production and the role of IL-10 during murine endotoxemia. We found that LPS injection causes the rapid release of IL-10, peak IL-10 serum levels being observed 90 min after LPS challenge. Neutralization of endogenously produced IL-10 by administration of 2 mg JES5-2A5 anti-IL-10 monoclonal antibody (mAb) 2 h before LPS challenge resulted in a marked increase in both TNF and IFN-gamma serum levels while irrelevant isotype-matched mAb had no effect. The enhanced production of inflammatory cytokines in anti-IL-10 mAb-treated mice was associated with a 60% lethality after injection of 500 micrograms LPS, while all mice pretreated with control mAb survived. We conclude that the rapid release of IL-10 during endotoxemia is a natural antiinflammatory response controlling cytokine production and LPS toxicity.
There is evidence that interleukin -10(IL-10) interferes with the costimulatory properties of antigen-presenting cells and, thereby, inhibits their ability to induce T cell activation. To determine whether this effect might involve modulation of the expression of accessory molecules, we analyzed by flow cytometry the influence of human IL-10 on the basal expression of intercellular adhesion molecule 1 (ICAM-1) as well as on the interferon gamma (IFN-gamma)-induced up-regulation of ICAM-1 and B7 at the surface of human monocytes. IL-10 inhibited both the basal expression and the IFN-gamma-induced ICAM-1 up-regulation. IL-10 also reduced B7 up-regulation on IFN-gamma-stimulated monocytes. The inhibitory effect of IL-10 both on ICAM-1 and B7 expression was shown to be dose dependent. We conclude that the ability of IL-10 to decrease both ICAM-1 and B7 expression on monocytes might contribute to its immunosuppressive properties.
Most of the immunosuppressive effects of interleukin-10 (IL-10) are related to functional inhibition of antigen-presenting cells (APC). Herein, we investigate the influence of recombinant (r)IL-10 on human dendritic cells (DC) purified from peripheral blood of healthy volunteers. First, we found that rIL-10 inhibited in a dose-dependent manner the proliferative responses as well as the production of IL-2 and interferon-gamma (IFN-gamma) in mixed lymphocyte reaction (MLR) between purified T cells and DC. This rIL-10 effect could be attributed to a direct effect on DC, as DC preincubated with rIL-10 were found to be deficient in the induction of alloreactive T cells even when anti-IL-10 neutralizing mAb was added at the time of MLR. Flow cytometric analysis indicated that rIL-10 did not modify the expression of ICAM-1 (CD54) and B7-1 (CD80), but decreased HLA-DR and B7-2 (CD86) expression at the DC surface. We conclude that the inhibitory effect of rIL-10 on primary alloreactive T cell responses involves down-regulation of class II MHC and B7-2 expression at the DC surface.
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