IL-1 pretreatment prolongs survival in lethal infection in normal and in neutropenic mice. We investigated whether this protection occurs by interference with deleterious cytokine effects. The effect of IL-1 pretreatment on concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha circulating in vivo and the ex vivo cytokine production capacity of macrophages was assessed in uninfected, non-neutropenic and neutropenic Swiss mice, in Swiss mice infected with Klebsiella pneumoniae (non-neutropenic mice) or Pseudomonas aeruginosa (neutropenic mice), and in neutropenic C3H/HeN and C3H/HeJ mice infected with P. aeruginosa. In Swiss and C3H/HeN mice, IL-1 pretreatment enhanced survival and reduced circulating TNF-alpha and IL-6 as well as LPS-stimulated production of IL-1 alpha and TNF-alpha. In C3H/HeJ mice, a lack of IL-1-induced protection was associated with low cytokine concentrations and production. In contrast, up-regulation of mRNA for the IL-1 receptor antagonist (IL-1Ra) was observed in several organs of IL-1-pretreated mice, suggesting that IL-1Ra could attenuate deleterious IL-1 effects. In addition, IL-1 pretreatment down-regulated steady state mRNA for the type I IL-1R and the type I TNFR in several organs at the time of infection, suggesting desensitization of target cells as an additional mechanism of IL-1-induced protection. We conclude that the IL-1-induced protection is at least partially mediated by down-regulating cytokine production, and that the induction of IL-1Ra and the desensitization of target cells by receptor down-modulation may also contribute to this phenomenon.