Interleukin-1, but not stress, stimulates glucocorticoid output during early postnatal life in mice.

The development of neuroendocrine functions depends not only on genetically determined mechanisms but also on phenotypic signals. Some of these signals may derive from the immune system. For example, interleukin-1 beta (IL-1 beta) stimulates glucocorticoid output during the early postnatal period, and administration of this cytokine at birth induces permanent alterations in the HPA axis in adulthood. We have extended these studies and found that the glucocorticoid response elicited in 5-day-old mice by a low dose of IL-1 beta is not desensitized by previous exposure to the cytokine. We have also compared the magnitude of the increase in corticosterone levels induced by IL-1 in 3-day-old and adult mice to that caused by acute stress. IL-1 beta and acute stress caused a comparable increase in corticosterone levels in adult mice. In newborn mice, however, IL-1 beta, but not restraint or cold stress, stimulated corticosterone output. Thus, IL-1 beta can elicit a corticosterone response during the postnatal stress-hyporesponsive period. Furthermore, when the corticosterone levels attained following IL-1 beta administration were compared to the basal levels of the hormone at a given age, the increase in plasma corticosterone levels was several fold higher in newborn than in adult animals. These data, together with the long-lasting endocrine effects of cytokine exposure at birth, suggest an important role of immune cytokines in the programming of neuroendocrine functions during ontogeny.

Central and peripheral mechanisms contribute to the hypoglycemia induced by interleukin-1.

The impact that neuroendocrine effects of cytokines have on general host homeostasis is reflected by the profound metabolic changes observed in parallel. The effect of interleukin-1 beta (IL-1 beta) on glucose blood levels serves as an example. Although IL-1 beta stimulates glucocorticoid output and decreases hepatic glycogen content, hypoglycemia is concomitantly detected in adult and newborn mice. This effect is observed even during fasting and is probably due to increased glucose transport into tissues. Even after a glucose load, IL-1-treated animals remain hypoglycemic, suggesting that central mechanisms that control the set point of glucose homeostasis are affected. Low doses of IL-1 beta injected i.c.v. can also induce hypoglycemia. Furthermore, central blockade of IL-1 receptors partially inhibits the hypoglycemia induced by peripheral administration of IL-1 beta. On the other hand, central depletion of catecholamines exacerbates IL-1-induced hypoglycemia. IL-1-mediated effects on glucose levels might be directed at providing more energy supply to tissues during processes with high metabolic demands.

Alterations in the pituitary-adrenal axis of adult mice following neonatal exposure to interleukin-1.

Interleukin-1 (IL-1), a cytokine mainly derived from activated cells of the macrophage lineage, can stimulate the hypothalamus-pituitary-adrenal (HPA) axis. Acute and long-lasting effects on the HPA axis were induced by the administration of low doses of IL-1 to mice during the first 5 days of life. In 5-day-old mice, corticosterone blood levels were markedly elevated 2 h following the last injection of IL-1. IL-1-treated mice grew normally. When studied during adulthood, however, these animals showed a reduction in morning values of corticosterone and the ACTH/corticosterone ratio was increased. Furthermore, an inverse correlation between ACTH and corticosterone levels in blood and between ACTH content in the pituitary gland and corticosterone levels was observed in IL-1-treated mice. Lower blood levels of corticosterone were not due to a reduced sensitivity of the adrenal glands, because these animals responded normally to exogenous ACTH. Another alteration observed in IL-1-exposed adult mice was a reduction in ACTH-like immunoreactivity in the pituitary gland following acute cold and restraint stress. It is concluded that exposure of mice to IL-1 early in life causes long-lasting alterations in the HPA axis. Spleen cells from adult mice treated with IL-1 at birth also developed a stronger response to allogeneic antigens than did cells from control mice. This observation indicates the relevance of immune-neuroendocrine interactions during development.

Metabolic and endocrine effects of interleukin-1 in obese, diabetic Zucker fa/fa rats.

IL-1, a cytokine produced predominantly by cell from the macrophage lineage, can affect multiple neuroendocrine and metabolic functions. We report here effects of this cytokine in obese, diabetic Zucker fa/fa rats. These animals are modestly hyperglycemic, hyper-lipemic, and markedly hyperinsulinemic. Changes in the levels of glucose, lactate, triglycerides, free fatty acids, insulin, glucagon, and corticosterone were detected following a single intraperitoneal or intravenous injection of IL-1 into fa/fa rats. No comparable changes were observed following administration of insulin. In fa/fa rats, the diabetic status is particularly manifested by an abnormal glucose tolerance. Administration of a bolus injection of IL-1 normalized the response of diabetic fa/fa rats to a glucose load. These rats not only returned to their basal glucose levels quicker, but reached glucose concentrations in blood which were comparable to, or even lower than those of Fa/? rats. Although the mechanism underlying the effects of IL-1 in fa/fa rats are presently not clear, the results obtained suggest that this cytokine tends to normalize glucose homeostasis and stimulate fat mobilization in these animals.

Cytokines as modulators of the hypothalamus-pituitary-adrenal axis.

The hypothalamus-pituitary-adrenal (HPA) axis is stimulated during the course of certain immune, inflammatory and neoplastic processes. IL-1 is an important immunologically derived cytokine mediating the stimulation of this axis, although not the only one. We have compared the relative potencies of the cytokines IL-1, IL-6 and tumor necrosis factor (TNF), which share several biological actions, for stimulating ACTH and corticosterone output in freely-moving rats. Although all three cytokines can stimulate the HPA axis, IL-1 was the most potent. This effect of IL-1 was also present during the neonatal period, when the response of the HPA axis to acute stress is reduced in rodents. The results support the existence of an immune-HPA axis circuit. The biological and clinical relevance of this circuit is discussed.