Defective tolerance to the toxic and metabolic effects of interleukin 1.
The effect on food intake, body weight, and survival of mice given recombinant lipopolysaccharide (LPS), tumor necrosis factor/cachectin (TNF), or interleukin 1 (IL-1) (5 micrograms/mouse, ip, twice daily) was studied. All agents induced a rapid reduction of food intake and body weight after 1 day of treatment. Unlike TNF and LPS, IL-1 given as two daily administrations of 5 micrograms was lethal within 3 days. Mice treated with LPS or TNF rapidly developed tolerance to their anorectic effect, whereas tolerance to IL-1 required a longer time to develop and was not complete. We investigated the possible roles of changes in serum corticosterone and glucose in the effects of LPS, TNF and IL-1. A single injection of LPS, TNF, or IL-1 markedly increased serum corticosterone levels after 2 h. After only 2 days of chronic treatment, mice given LPS or TNF were refractory to induction of serum corticosterone by a subsequent injection of LPS or TNF, but mice given IL-1 for 2 days were still fully responsive to IL-1. IL-1, unlike TNF and LPS, induced a marked hypoglycemic response. Repeated administration of IL-1 sensitized to its hypoglycemic effect. This lack of adaptation to the increase of serum corticosterone and hypoglycemia was also observed when IL-1 was given at lower, nonlethal doses (0.25-1.0 microgram) and for a longer period (up to 8 days). The defective tolerance to the metabolic and toxic effects of IL-1 in this experimental model indicates that there are major differences between the in vivo biological responses to IL-1 and TNF.
Mengozzi
M
M
Laboratory of Immunology, Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.
Ghezzi
P
P
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood*; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects; D007003:Hypoglycemia / Q000139:chemically induced*; D007375:Interleukin-1 / Q000009:adverse effects* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone