DIFFERENTIAL GENE-EXPRESSION FOR IL-1 RECEPTOR ANTAGONIST, IL-1, AND TNF RECEPTORS AND IL-1 AND TNF SYNTHESIS MAY EXPLAIN IL-1-INDUCED RESISTANCE TO INFECTION
Mte. Vogels et al., DIFFERENTIAL GENE-EXPRESSION FOR IL-1 RECEPTOR ANTAGONIST, IL-1, AND TNF RECEPTORS AND IL-1 AND TNF SYNTHESIS MAY EXPLAIN IL-1-INDUCED RESISTANCE TO INFECTION, The Journal of immunology, 153(12), 1994, pp. 5772-5780
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 pr
etreatment on concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-a
lpha circulating in vivo and the ex vivo cytokine production capacity
of macrophages was assessed in uninfected, non-neutropenic and neutrop
enic Swiss mice, in Swiss mice infected with Klebsiella pneumoniae (no
n-neutropenic mice) or Pseudomonas aeruginosa (neutropenic mice), and
in neutropenic C3H/HeN and C3H/HeJ mice infected with P. aeruginosa. I
n Swiss and C3H/HeN mice, IL-1 pretreatment enhanced survival and redu
ced circulating TNF-alpha and IL-6 as well as LPS-stimulated productio
n 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 produc
tion. In contrast, up-regulation of mRNA for the IL-1 receptor antagon
ist (IL-1Ra) was observed in several organs of IL-1-pretreated mice, s
uggesting that IL-1Ra could attenuate deleterious IL-1 effects. In add
ition, 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 infectio
n, suggesting desensitization of target cells as an additional mechani
sm of IL-1-induced protection. We conclude that the IL-1-induced prote
ction is at least partially mediated by down-regulating cytokine produ
ction, and that the induction of IL-1Ra and the desensitization of tar
get cells by receptor down-modulation may also contribute to this phen
omenon.