Tumor cell IL-6 gene expression is regulated by IL-1 alpha/beta and TNF alpha: proposed feedback mechanisms induced by the interaction of tumor cells and macrophages.
In the present report, we show that progressive growth of the immunogenic C57BL/6J sarcoma, MCA/76-9, was accompanied by an increase in serum interleukin-6 (IL-6) activity. The possible pathways leading to the induction of IL-6 release by the tumor cells are described. It was shown that macrophage products IL-1 alpha, IL-1 beta, and to a lesser extent, TNF alpha, induced the tumor cells in vitro to transcribe the IL-6 gene and release the gene product. IL-1 induced significantly more IL-6 mRNA and bioactivity than TNF alpha, although both cytokines induced a cumulative increase of bioactivity in the supernates over a period of 24 h. The tumor cells were shown to express receptors for IL-1 alpha, which could be blocked with anti-IL-1 receptor antibody. Given the previous reports that tumor-associated macrophages expressed both IL-1 alpha/beta and TNF alpha, the data suggest, first, that the mutual interaction of tumor cells and macrophages in situ may contribute to the observed increase in circulating IL-6 activity, and second, that the release of IL-6 in vivo may serve to regulate both anti-tumor immune responses and suppressor mechanisms.
Evans
R
R
Jackson Laboratory, Bar Harbor, ME 04609.
Fong
M
M
Fuller
J
J
Kamdar
S
S
Meyerhardt
J
J
Strassmann
G
G
D000818:Animals; D002455:Cell Division / Q000502:physiology; D005246:Feedback; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000378:metabolism / Q000502:physiology; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha