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.
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.
Vogels
M T
MT
Department of Medicine, University Hospital, Nijmegen, The Netherlands.
Mensink
E J
EJ
Ye
K
K
Boerman
O C
OC
Verschueren
C M
CM
Dinarello
C A
CA
van der Meer
J W
JW
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007710:Klebsiella Infections / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D011552:Pseudomonas Infections / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D011863:Radioimmunoassay; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha