Modulation of interleukin-1 receptors in the neuro-endocrine-immune axis.

Interleukin-1 (IL-1) receptors with kinetics, pharmacological and biochemical characteristics of type I IL-1 receptors have been identified in the mouse neuro-endocrine-immune axis. In the present study, we examined the in-vitro and in-vivo modulation of IL-1 receptors by stress and endotoxin treatment. The treatment of AtT-20 mouse pituitary adenoma cells for 24 hr with neuro-endocrine mediators of stress such as corticotropin releasing factor (CRF) and catecholamine (beta 2 adrenergic) receptor agonists produced a dose-dependent increase in cAMP and [125I]IL-1 alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated cAMP production and decreased both basal and CRF-mediated increase of [125I]IL-1 alpha binding. Furthermore, in keeping with the effects of stress mediators to upregulate IL-1 receptors in AtT-20 cells, ether-laparotomy stress in mice resulted in a significant increase in [125I]IL-1 alpha binding in the pituitary with no significant alterations observed in the brain; in contrast, [125I]oCRF binding in the pituitary was significantly decreased after the ether-laparotomy stress. Next, we investigated the modulation of IL-1 beta levels and [125I]IL-1 alpha binding following endotoxin lipopolysaccharide (LPS) treatment. IL-1 beta levels were dramatically increased in the peripheral tissues (pituitary, testis and spleen) at 2-6 hr after a single LPS injection (30 micrograms LPS/mouse). However, no significant changes were observed in brain (hippocampus and hypothalamus). [125I]IL-1 alpha binding in the pituitary gland, liver, spleen and testis was significantly decreased at 2 hr following a single administration of both low (30 micrograms LPS/mouse) and high (300 micrograms LPS/mouse) doses of endotoxin. [125I]IL-1 alpha binding in the hippocampus was not significantly altered at 2 hr by a low dose of LPS and was significantly decreased by high dose administration of LPS (300 micrograms/mouse). Following two LPS injections (at 0 and 12 hr), dramatic increases in IL-1 beta concentrations in the hypothalamus, hippocampus, spleen and testis were observed at 2 hr after the second LPS injection; a small but statistically nonsignificant change was evident in the pituitary. Moreover, dramatic decreases in [125I]IL-1 alpha binding were seen after two injections of 30 micrograms LPS/mouse in both central and peripheral tissues. These data provide further support for a role for IL-1 in co-ordinating neuro-endocrine-immune responses to stress and infection.