Differential Effects of One and Repeated Endotoxin Treatment on Pituitary- Adrenocortical Hormones in the Mouse: Role of Interleukin-1 and Tumor Necrosis Factor-α

Abstract

The role of endogenous interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in modulating the hypothalamic-pituitary-adrenal (HPA) axis response was examined in male C57BL/6 mice injected with endotoxin (lipopolysaccharide, LPS) or saline at 24-hour intervals for 4 or 8 consecutive days. The mice were divided into four groups: (1) LPS injections for 4 or 8 days and LPS injection on day 5 or 9, respectively (LPS-LPS); (2) LPS injections for 4 or 8 days and saline injection on day 5 or 9, respectively (LPS-saline); (3) saline injections for 4 or 8 days and LPS injection on day 5 or 9, respectively (saline-LPS), and (4) saline injections for 4 or 8 days and saline injection on day 5 or 9 (saline-saline). The mice were sacrificed by decapitation 2 h after the last injection and plasma levels of hormones and cytokines and tissue levels of IL-1β were measured. Plasma adrenocorticotropin (ACTH) levels were significantly attenuated in the LPS-LPS group compared with the dramatic increases in the saline-LPS group following 4 or 8 days of endotoxin treatment. Plasma corticosterone concentrations were comparable in the LPS-LPS group after 4 days’ treatment, but significantly lower following 8 days of treatment when compared with saline-LPS group. Repeated endotoxin treatment followed by a single saline injection (LPS-saline) did not alter the levels of IL-1β in plasma or any of the tissues examined. IL-1β levels in the hippocampus, hypothalamus, adrenal gland and plasma were elevated to comparable levels in the saline-LPS and LPS-LPS groups after 4 days of treatment. In contrast to the plasma IL-1β response, TNFα levels were dramatically increased in the saline-LPS group but not in the LPS-LPS group following the 4-day treatment regimen. Increases in IL-1β concentrations were seen in all tissues following one endotoxin challenge in the saline-LPS group following the 8-day treatment regimen, while increases were significantly attenuated in the hypothalamus, adrenal gland and plasma in LPS-LPS for 8 days. The sustained increases in tissue levels of IL-1β following 4-day endotoxin treatment appears to have functional consequences since [¹²⁵I]IL-1α binding was significantly decreased in the LPS-saline group compared with the saline-saline group. Furthermore, [¹²⁵I]IL-1α binding was markedly reduced in the LPS-LPS group compared with the saline-LPS group. There was a significant positive correlation between plasma ACTH and IL-1β after a single and repeated LPS treatment for 4 days, while a significant correlation was seen between plasma ACTH and TNFα following one but not repeated LPS treatment. These data demonstrate a differential regulation of IL-1β and TNFα by repeated endotoxin treatment and suggest that while TNFα may be important modulating the attenuated pituitary adrenocortical response following the 4-day endotoxin treatment, IL-1β appears to be the primary regulator of the response following the 8-day endotoxin treatment in the regulation of the HPA axis.

Acute diclofenac treatment attenuates lipopolysaccharide-induced alterations to basic reward behavior and HPA axis activation in rats

“…In the current report, LPS exposure induced plasma IL-1β release and increased IL-1β and IL-6 gene expression in hippocampus in salinetreated and diclofenac-treated rats. The cytokine activation responses in the current report are similar to those previously reported following acute LPS and IL-1β exposure (Laye et al 1994;Lenczowski et al 1997;Nagano et al 1999;Turrin et al 2001). The current data may coincide with a recent report showing that an NSAID attenuated anorexia during systemic inflammation without impairing cytokine production (Johnson et al 2002).…”

Modulation of Interleukin-1 Receptors Followed by Endotoxin Lipopolysaccharide Treatment in the Mouse AtT-20 Pituitary Tumor Cell Line

“…The present results clearly demonstrate that the decrease of IL-1 receptors in vivo is not due to a direct effect of LPS since IL-1 receptors are increased in AtT-20 cells in vitro while available receptors in vivo are decreased followed by LPS treatment. Our previous studies demonstrated that IL-1ß concentrations were increased in plasma and in the hippocampus, pituitary, adrenal gland 2 h after LPS injection [14,25], suggesting that high ligand concentrations remained in the tissues. Furthermore, 1 nM IL-1ß significantly decreased IL-1 receptors in AtT-20 cells compared with the control group in the present study, supporting that the rather high ligand concentration causes receptor occupancy and downregulation.…”

Effect of Orchidectomy on the Age-Related Modulation of IL-1β and IL-1 Receptors following Lipopolysaccharide Treatment in the Mouse

“…On the other hand, LPS significantly stimulated adrenal IL-1ß production in 24-week-old mice compared with the saline group. Of the three tissues (hippocampus, hypothalamus and adrenal gland) examined, basal concentrations of IL-1ß were, by far, highest in the adrenal gland, followed by the hypothalamus and hippocampus [40]. In the present study, saline-induced (basal) IL-1ß concentrations in the adrenal gland were approximately 25-40 times higher than those in the hippocampus and hypothalamus, which may be responsible for the differences in the agerelated modulation of IL-1ß levels by LPS in 7-and 24-week-old mice.…”