Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism

Neuroendocrine and neurochemical responses were studied following administration of recombinant mouse IL-6 (mIL-6) to mice. Intravenous (iv) or intraperitoneal (ip) injection of mIL-6 caused a rapid and short-lived activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, as indicated by increases in plasma ACTH and corticosterone, with peak responses around 30-60 min. These responses contrast with those to ip mIL-1beta which is substantially more potent and induces a greater response which does not peak until about 2 h following ip administration. Unlike IL-1 and lipopolysaccharide (LPS), IL-6 had no detectable effect on norepinephrine metabolism. However, tryptophan concentrations were elevated in most brain regions studied 1-2 h following iv mIL-6, and 2 h following ip mIL-6, significantly later than the peak HPA response. 5-hydroxyindoleacetic acid (5-HIAA) and the ratio of 5-HIAA to serotonin (5-HT) were elevated at around the same time in the brain stem, and occasionally in other brain regions. These responses were observed at doses of mIL-6 as low as 0.25 microg, and near maximal effects were achieved by 0.5 microg. Recombinant human IL-6 elicited similar responses, but was significantly less potent. Heat-treated mIL-6 elicited none of the responses. Serum amyloid A protein (SAA) concentrations were not elevated until 4 h after iv or ip mIL-6 administration, suggesting that the neuroendocrine and neurochemical changes were not secondary to an acute phase protein response. Intracerebroventricular injection of mIL-6 also elevated tryptophan and 5-HIAA in the hypothalamus and brain stem. Pretreatment of mice with the cyclooxygenase inhibitor, indomethacin, or the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) did not attenuate the mIL-6 induced neuroendocrine or neurochemical responses. However, the ganglionic blocking drug, chlorisondamine, prevented the increases in tryptophan and 5-HIAA:5-HT ratios. IL-6 may contribute to the HPA and indoleaminergic responses to LPS and IL-1. It is possible that the increases of tryptophan and serotonin metabolism may contribute to some of the biological effects of IL-6.