Roles of interleukin-1 alpha and -1 beta in endotoxin-induced suppression of plasma gonadotropin levels in rats.

Abstract

Using specific antagonists to rat interleukin (IL)-1 alpha and IL-1 beta, the roles of these IL-1s in endotoxin-induced suppression of plasma gonadotropin levels in freely-moving rats were studied. In orchiectomized rats, recombinant rat IL-1 alpha and IL-1 beta administered into the lateral ventricles almost equipotently suppressed plasma LH levels. Twenty five micrograms of bacterial endotoxin or lipopolysaccharide (LPS) administered similarly showed a comparable effect as that of 1 microgram IL-1 alpha or IL-1 beta, and completely lowered plasma LH levels by 60 min after the injection. To examine the roles of endogenous IL-1 alpha and IL-1 beta, anti-rat IL-1 alpha antiserum (anti-IL-1 alpha) and a recombinant human IL-1 receptor antagonist (IL-1ra) were used as specific blockers for IL-1 alpha and IL-1 beta, respectively. Anti-IL-1 alpha (10 microliters) or IL-1ra (10 micrograms) administered intracerebroventricularly (icv) with 25 micrograms LPS, significantly attenuated the LPS-induced effect on plasma LH levels during the first 60 min after LPS infusion, but not during the second 60 min. LPS at a dose of 5 micrograms induced smaller but still significant changes in plasma LH levels compared with 25 micrograms LPS or 1 microgram IL-1 beta. IL-1ra (10 micrograms) completely blocked LH suppression induced by 1 microgram IL-1 beta, but did not completely reverse the changes of LH induced by 5 micrograms LPS. IL-1ra injected iv also significantly attenuated the early suppressive effect of iv administered LPS, but not its late effect on plasma LH levels. However, iv administered IL-1ra had no influence on the effects of icv administered LPS. These data indicate that at least a part of plasma LH suppression caused by icv administered LPS is mediated via IL-1 alpha and IL-1 beta synthesized within the brain, while factor(s) other than IL-1 also participate in the LPS-induced change, particularly during the later period. A similar mechanism may also work peripherally in the case of iv administered LPS-induced plasma LH suppression.

Inhibitory Effects of Endotoxin on LH Secretion in the Ovariectomized Monkey Are Prevented by Naloxone but Not by an Interleukin-1 Receptor Antagonist

“…Our conclusion in the non-human primate is different from data in the rodent in which IL-1ra was shown to interfere with LPS-induced ACTH and corticosterone release [16,24]. However, also in the rodent [25], IL-1ra appears to be capable only of attenuating the LH inhibitory effects of intracerebroventricular LPS during the first 60 min but not thereafter, suggesting that, if any, the role of IL-1 in mediating these effects of LPS on LH secretion is limited. No early effects of IL-1ra were observed in the monkey, perhaps reflecting varying experimental conditions or a species-specific difference.…”

Immune stress up regulates <i>TLR4</i> and <i>Tollip</i> gene expression in the hypothalamus of ewes

“…Central injections of LPS have been shown to induce brain expression of pro-inflammatory cytokines and to depress social behavior in rats, increase the duration of immobility, and induce body weight loss (Bluthé et al, 1999). Moreover, endotoxin given experimentally to the brain region affected the functioning of the central nervous system and led to strong suppression of the peripheral LH level (Ebisui et al, 1992). A study performed on chimeric mice showed that TLR4 is crucial for sustained inflammation in the brain after peripheral administration of LPS and that its function in CNS-resident cells is independent of systemic cytokine effects (Chakravarty and Herkenham, 2005).…”

Lipopolysaccharide-Induced Suppression of the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator in Ovariectomized Goats.

“…Although the reason for this paradoxical effect on LH secretion is unclear, this might be caused by a direct action of LPS on the pituitary as suggested from in vitro experiment [4]. In laboratory rodents, recent studies on the neural mechanism underlying the immunological suppression of basal LH secretion and the preovulatory LH surge release [2,6,9,10,14,[19][20][21][22]27] have led to a concept outlined as follows. First, peripheral immune cells are activated following the immunological challenge like the LPS administration, and a number of cytokines are released from these cells.…”

“…Considerable efforts have been made to clarify the mechanism underlying this suppression, and it has been revealed that an immunological activation of host animal results in a reduction of luteinizing hormone (LH) secretion from the pituitary gland and/or direct suppression of gonadal function in several species [4,8,14,18,[23][24][25]27]. In rodents, for instance, the administration of lipopolysaccharide (LPS), an endotoxin of gram negative bacteria, or cytokines released from immune cells during the acute phase of infection suppresses secretion of gonadotropin-releasing hormone (GnRH) and LH [2,6,9,10,19]. This inhibitory effect on the hypothalamic-pituitary gonadal (HPG) axis is thought to be mediated by the mechanism which is independent from that for the activation of hypothalamic-pituitary adrenal (HPA) axis [20,23].…”