INTERLEUKIN-10 CONTROLS INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR PRODUCTION DURING EXPERIMENTAL ENDOTOXEMIA

Interleukin-10 (IL-10) is a potent inhibitor of lipopolysaccharide (LP S)-induced tumor necrosis factor (TNF) production and has been shown t o protect mice from endotoxin shock. As IFN-gamma is another important mediator of LPS toxicity, we studied the effects of IL-10 on LPS-indu ced 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 neutral ization of endogenously synthesized IL-10 resulted in increased IFN-ga mma levels. The ability of rIL-10 to inhibit LPS-induced IFN-gamma syn thesis was also observed in vivo in mice. Indeed, administration of 10 00 U recombinant mouse IL-10 (rmIL-10) 30 min before and 3 h after cha llenge of BALB/c mice with 100 mu g LPS resulted in a threefold decrea se in peak IFN-gamma serum levels. We then examined the production and the role of IL-10 during murine endotoxemia. We found that LPS inject ion causes the rapid release of IL-10, peak IL-10 serum levels being o bserved 90 min after LPS challenge. Neutralization of endogenous ly pr oduced 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-matche d mAb had no effect. The enhanced production of inflammatory cytokines in anti-IL-10 mAb-treated mice was associated with a 60 % lethality a fter injection of 500 mu g LPS, while all mice pretreated with control mAb survived. We conclude that the rapid release of IL-10 during endo toxemia is a natural antiinflammatory response controlling cytokine pr oduction and LPS toxicity.