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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.

The cytokine interleukin-1 (IL-1) alters a variety of immune, central nervous system and neuroendocrine activities characteristic of an integrator of the brain-endocrine-immune response to stress. In an attempt to define the regulation of IL-1 and IL-1 receptors in the mouse brain-endocrine-immune axis during maturation, we measured tissue levels of IL-lβusing an ELISA and iodine- 125-labeled recombinant human interleukin-1α([¹²⁵I]IL-lα) binding in hippocampus, pituitary, testis and spleen following intraperitoneal injection of saline or the bacterial endotoxin, lipopolysaccharide (LPS) in 3- and 24-week-old C57BL/6 mice. Basal IL-lβlevels were detectable in all the tissues examined. Basal levels of IL-1β in the hippocampus, spleen and testis in 24-week-old mice were significantly higher than those in 3-week-old mice. [¹²⁵I]IL-lαbinding was detectable in all the mouse tissues examined and [¹²⁵I]IL-1αbinding levels in the pituitary, spleen and testis in 3-week-old mice were significantly higher than those in 24-week-old mice. To further evaluate the modulation of IL-1 receptors in aging, we measured [¹²⁵I]IL-1αbinding in 2-, 5-, 10-, 18-, and 24-month-old mice. [¹²⁵I]IL-1αbinding in testis in 24-month-old mice was higher than the other groups; [¹²⁵I]IL-1αbinding in the hippocampus and spleen was unchanged during these periods. Dramatic increases in IL-lβconcentrations were observed at 2 h after LPS injection in the pituitary, spleen, testis and plasma in both 3- and 24-week-old mice groups. In contrast, IL-lβlevels in the hippocampus increased in response to LPS injection only in 24-week-old mice. [¹²⁵I]IL-1αbinding in hippocampus was significantly decreased in 24- but not in 3-week-old mice after LPS injection. [¹²⁵I]IL-1αbinding in the spleen and testis were significantly decreased in both age groups following LPS administration. These data demonstrate differential regulation of IL-1 and its receptors in the brain-endocrine-immune axis during maturation and in response to endotoxin challenge.

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