Synergism between IL-1 beta and TNF-alpha on the activity of the pituitary-adrenal axis and on food intake of rats

M. J. Van der Meer, C. G. Sweep, G. J. Pesman, G. F. Borm and A. R. Hermus Department of Endocrinology, University Hospital Nijmegen, The Netherlands. We investigated the effects of separate and combined intraperitoneal administration for 3 days of recombinant human interleukin-1 beta (IL-1) and recombinant human tumor necrosis factor-alpha (TNF) on plasma adrenocorticotropic hormone (ACTH) and corticosterone (B) levels, adrenal weight, food intake, and rectal temperature. Rats were equipped with a jugular cannula for daily blood sampling and with an intraperitoneally implanted Alzet osmotic minipump loaded with either saline, IL-1 (2.0 micrograms/day), TNF (0.2, 2.0, or 10.0 micrograms/day), or IL-1 in combination with TNF. Plasma ACTH and B levels and adrenal weight were significantly increased, in a dose-dependent way, by simultaneous infusion of IL-1 and TNF but not by administration of either cytokine alone. Chronic administration of IL-1 alone induced a significant decrease in food intake and a significant elevation of rectal temperature, whereas infusion of only the highest dose of TNF significantly elevated rectal temperature. Coinfusion of IL-1 and TNF induced both effects in a dose-dependent and synergistic way. Our data show that simultaneous infusion of IL-1 and TNF in rats has a synergistic effect on the activity of the pituitary-adrenal axis as well as on food intake and rectal temperature. The existence of two pathways, which act synergistically, may increase the sensitivity of the host to respond to subtle inflammatory stimuli.