In vivo induction of IL-6 by administration of exogenous cytokines and detection of de novo serum levels of IL-6 in tumor-bearing mice.
We investigated the capacity of several recombinant cytokines to induce IL-6 in vivo in both normal and tumor-bearing (TB) mice. Intravenous administration of human rhTNF-alpha, rhIL-1, rhIL-2, rhIFN-alpha A/D, and rmIFN-gamma were all capable of inducing circulating IL-6. rhTNF-alpha administration caused the greatest induction of IL-6. TB animals consistently produced more IL-6 in response to rhTNF-alpha than did normal mice (2 h after 4 micrograms rhTNF-alpha, TB = 24,100 HGF U/ml, non-TB = 3600 HGF U/ml of IL-6). A single daily i.v. dose of rhTNF-alpha (4 micrograms/mouse/day) for 5 days led to decreased IL-6 induction in TB animals by day 3 of treatment (peak levels of IL-6, day 1 = 72,800 HGF U/ml, day 3 = 23,400 HGF U/ml, day 5 = 26,400 HGF U/ml). rhIL-1 administration also resulted in considerable IL-6 production, although peak values were less than those resulting from administration of rhTNF-alpha. Administration of rhIL-1 induced similar IL-6 levels (TB = 10,025 and non-TB = 10,600 HGF U/ml) in TB and normal mice. Single high doses of rhIL-2, rhIFN-alpha A/D, and rmIFN-gamma induced lower but consistent levels of circulating IL-6 in mice with and without tumor. In addition, the sera of untreated TB mice contained levels of IL-6 which paralleled the extent of tumor burden (serum IL-6 in day 30 MCA 106 TB mice = 420 HGF U/ml). The detection of de novo IL-6 was also confirmed in animals bearing tumors of different histologies (the MCA 102 sarcoma, MCA 38 adenocarcinoma, and B16 melanoma). At no time was IL-6 measurable in the sera of untreated normal mice. The identification of IL-6 was verified by neutralization studies using specific antimurine IL-6 antibody. Although the exact role of IL-6 in TB animals remains to be elucidated, its known pleotrophic immune and metabolic effects may be important in the host response to malignancy.
McIntosh
J K
JK
Surgery Branch, National Cancer Institute, Bethesda, MD 20892.
Jablons
D M
DM
Mulé
J J
JJ
Nordan
R P
RP
Rudikoff
S
S
Lotze
M T
MT
Rosenberg
S A
SA
D000230:Adenocarcinoma / Q000097:blood / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001685:Biological Factors / Q000008:administration & dosage*; D002455:Cell Division; D016207:Cytokines; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage; D007371:Interferon-gamma / Q000008:administration & dosage; D007375:Interleukin-1 / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D015850:Interleukin-6; D007378:Interleukins / Q000096:biosynthesis* / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage; D012513:Sarcoma, Experimental / Q000097:blood / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D001685:Biological Factors; D016207:Cytokines; D007370:Interferon Type I; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D007378:Interleukins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma