Interleukin 2 induces tumor necrosis factor gene expression in vivo.
Interleukin 2 (IL-2) treatment of malignancies is often associated with severe toxicity, and the alterations observed after high dose administration of IL-2 are similar to those induced by recombinant tumor necrosis factor (TNF). We therefore examined the hypothesis that IL-2 induces TNF gene expression in vivo. Purified, recombinant human IL-2 was injected intraperitoneally into mice which had been previously primed with complete Freund's adjuvant (CFA). Biologically-active TNF was detected in the ascites fluid of CD-1 mice; it was detectable 30 minutes after IL-2 and peaked at 1 hour (500 +/- 158 units/ml). Plasma levels of TNF also peaked at 1 hour at 32 +/- 4 units/ml. Similar kinetics were observed in CBA/J mice. TNF specific mRNA was also present in the ascites cells, and peaked 30 minutes after IL-2 injection into CBA/J mice. Injection of vehicle containing 10 times the maximum contaminating dose of endotoxin did not induce TNF above background levels. As a further control for potential endotoxin contamination, IL-2 was injected into endotoxin hyporesponsive C3H/HeJ mice. These mice also demonstrated the rapid upregulation of biologically-active TNF in the ascites, with peak production occurring at 1 hour (125 +/- 47 units/ml). The induction of biologically-active TNF in the C3H/HeJ mice was associated with a peripheral blood neutrophilia and lymphopenia, pathophysiologic alterations that have been attributed to TNF. These data show that a single injection of purified, recombinant IL-2 induces TNF gene expression in vivo.
Remick
D G
DG
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Nguyen
D T
DT
Eskandari
M K
MK
Kunkel
S L
SL
D000818:Animals; D001483:Base Sequence; D015870:Gene Expression / Q000187:drug effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000633:toxicity*; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D011089:Polydeoxyribonucleotides / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D007376:Interleukin-2; D011089:Polydeoxyribonucleotides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha