Cytokine Regulation of Corticosteroid Receptors in the Rat Hippocampus: Effects of Interleukin-1, Interleukin-6, Tumor Necrosis Factor and Lipopolysaccharide

The effects of interleukin-1 beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF) and lipopolysaccharide (LPS) on hippocampal corticosteroid receptors were studied in the rat. Type I (mineralocorticoid) and type II (glucocorticoid) receptors were measured in hippocampal cytosolic fractions with the radioligand binding technique, using 3H-corticosterone and 3H-RU 28362, respectively. LPS, administered intraperitoneally (50 micrograms/kg 8 h before sacrifice or 100 micrograms/kg injected twice, 16 and 8 h before sacrifice) to rats which had been previously adrenalectomized to allow for clearance of endogenous corticosterone, did not modify either type of corticosteroid receptors in the hippocampus. IL-1, IL-6, TNF or saline were injected intracerebroventricularly (50 ng/rat) and the animals were killed 3 h after. Type I receptors were not affected by any of the cytokines studied. Moreover, no changes in type II receptors were observed after IL-1 or IL-6 administration. In contrast, hippocampal type II receptors were dramatically decreased after the injection of TNF. The TNF-induced downregulation of type II receptors was secondary to a marked decrease in the affinity of the receptors (Kd increased 7.2-fold), accompanied by a 51% decrease in receptor number (Bmax). These results emphasize the important role played by TNF in the modulation of the hypothalamic-pituitary-adrenal axis during immune/inflammatory processes and extend the central sites of action of this cytokine to the corticosteroid receptors of the hippocampus.