Mechanism of acute toxicity of IL-1 beta in mice.
Human recombinant IL-1 beta was able to kill C3H/HeJ mice only when inoculated intravenously at very high doses. IL-1 beta, inoculated at 100 mg/kg i.v. as a bolus, induced a shock-like state characterized by anorexia, severe hypothermia and hypoglycemia and persistent neutrophilia, leading to death in 55% of animals generally between 24 and 48 h. In contrast, the noninflammatory adjuvant IL-1 beta peptide VQGEESNDK (position 163-171) did not induce any toxic effect in vivo, when administered following the same schedule. At variance with what was previously observed in endotoxin induced shock, IL-1 beta induced death was not preceded by appearance of circulating TNF. On the other hand, very high and persistent levels of circulating IL-6 could be detected after lethal IL-1 beta administration. Treatment of mice with ibuprofen or with chlorpromazine, both known to counteract some of the toxic effects of IL-1 in vivo, could protect from IL-1 beta induced mortality. Both drugs, at doses protecting from IL-1 beta induced death, were able to abolish IL-1 beta-induced rise of circulating phospholipase A2 (PLA2) activity, and the subsequent generation of toxic PLA2-derived metabolites.
Boraschi
D
D
Sclavo Research Center, Siena, Italy.
Villa
L
L
Ghiara
P
P
Tagliabue
A
A
Mengozzi
M
M
Solito
E
E
Parente
L
L
Silvestri
S
S
Van Damme
J
J
Ghezzi
P
P
D000595:Amino Acid Sequence; D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity*; D053583:Interleukin-1beta; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity; D010741:Phospholipases A / Q000096:biosynthesis; D054467:Phospholipases A2; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171); D010741:Phospholipases A; D054467:Phospholipases A2; D002746:Chlorpromazine; D007052:Ibuprofen