Tomoyasu Ichijo

Hypothalamic modulation of splenic natural killer cell activity in rats.

1. The cytotoxic activity of splenic natural killer cells measured by a standard chromium release assay in urethane and alpha‐chloralose‐anaesthetized rats was significantly suppressed 20 min after bilateral ablation of the medial part of the preoptic hypothalamus (MPO). The suppression was completely blocked by prior splenic denervation. The splenic natural killer cell activity of MPO sham‐lesioned rats or thalamus‐lesioned rats, both having an intact splenic innervation, were not different from that of a non‐treated control group. 2. Electrical stimulation of the bilateral MPO (0.1 ms, 0.1‐0.3 mA, 5‐100 Hz) suppressed the efferent activity of the splenic nerve in all six rats examined. The reduction of the nerve activity was accompanied by a transient fall in blood pressure. An I.V. injection of phenylephrine (3 micrograms/0.3 ml) also evoked a suppression of the nerve activity, which was accompanied by transient hypertension, suggesting that the suppressive effect of the MPO stimulation was independent of changes in blood pressure. On the other hand, a bilateral lesion of the MPO resulted in a sustained increase in the electrical activity of the splenic sympathetic nerve filaments which lasted for more than 2 h. 3. Microinjection of monosodium‐L‐glutamate (0.1 and 0.01 M in 0.1 microliters saline) unilaterally into the MPO evoked a transient suppression of the efferent discharge rate of the splenic nerve activity within 1 min, which was also accompanied by a decrease in blood pressure. The injection of saline (0.1 microliter) into the MPO had no effect. The microinjection of recombinant human interferon‐alpha (200 and 2000 U in 0.1 microliter saline) into the MPO dose dependently increased the splenic nerve activity without any change in blood pressure. 4. In contrast, microinjection of interferon‐alpha into the paraventricular nucleus of the hypothalamus (PVN) had no effect on splenic nerve activity, although an injection of glutamate increased the nerve activity. 5. The present results, taken together with previous reports, suggest that the neuronal networks between the MPO and the splenic sympathetic nerve, which may be activated by centrally administered interferon‐alpha, are important in the suppression of the splenic cellular immunity.

Central interleukin-1β enhances splenic sympathetic nerve activity in rats

Abstract The central administration of immune cytokines such as interleukin-1 (IL-1) and interferon-α (IFN-α) results in the suppression of peripheral cellular immunity, which depends, at least partly, on the sympathetic nervous activity. An intrathird cerebroventricular (I3V) infusion of recombinant human IL-1β (rhIL-1β) (1–5 ng/rat) elicited a dosedependent increase in the electrical activity of the splenic sympathetic nerve in urethane and α-chloralose anesthetized rats. The effect of rhIL-1β (1 ng/rat) was completely blocked by pretreatment with an IL-1 receptor antagonist (1 μg/rat, I3V 10 min before rhIL-1β), sodium salicylate (1 μg/rat), or α-melanocyte stimulating hormone (α-MSH) (400 ng/rat). Furthermore, an antagonist of corticotropin-releasing factor (CRF), α-helical CRF 9.41 (2 μg/rat), completely abolished the rhIL-1β-induced increase in the splenic nerve activity, although an I3V infusion of CRF (1 μg/rat) excited it. These results suggest that IL-1β in the brain activates splenic sympathetic activity by its receptor-mediated and prostaglandin-dependent action that is sensitive to α-MSH, depending on CRF system. Our findings, together with the previous results, suggest that the splenic sympathetic nerve represents one of the communication channels from the brain to the immune system.

The effect of interleukin-1β on the efferent activity of the vagus nerve to the thymus

The effects of intravenous (i.v.) administration of recombinant human interleukin-1 beta (rhIL-1 beta) and human interleukin-1 beta-fraction (hfrIL-1 beta) on the activity of vagal efferent fibers innervating the thymus were observed in urethane-anesthetized rats. An i.v. injection of 10 ng rhIL-1 beta or hfrIL-1 beta caused a similar degree of increase in the efferent activity, which lasted longer than 2 h. The least effective dose was 1 ng and dose-dependent responses were observed after i.v. injection of rhIL-1 beta at doses of 1 ng, 10 ng and 100 ng. The IL-1 beta-induced activation of efferent activity of the vagal branch to the thymus implicates their involvement in the neural modulation of the thymic function.

Sequential relationship between actions of CRF and PGE2 in the brain on splenic sympathetic nerve activity in rats

An infusion of corticotropin-releasing factor (CRF, 0.1-5.0 micrograms/10 microliters/rat) into the third cerebral ventricle (i.c.v.) for 10 min increased the splenic sympathetic nerve activity in a dose-dependent manner in urethane + alpha-chloralose anesthetized rats. No changes in the arterial blood pressure and body temperature were observed. The CRF (1.0 micrograms/10 microliters)-induced enhancement of the splenic sympathetic nerve activity was completely blocked by an i.c.v. pretreatment with a CRF antagonist, alpha-helical CRF9-41 (alpha-hCRF, 10 micrograms/10 microliters). The increase in the splenic sympathetic nerve activity induced by CRF was not blocked by pretreatment with a cyclooxygenase inhibitor, sodium salicylate (100 micrograms/10 microliters). In contrast, the splenic sympathetic nerve activity also increased after an i.c.v. injection of prostaglandin E2 (PGE2, 1 ng/10 microliters) and the increase was completely blocked by i.c.v. pretreatment with alpha-hCRF. These findings suggested a sequential relationship between actions of CRF and PGE2, with an activation of PGE2 system followed by that of CRF system in the brain resulting in an increase in the splenic sympathetic nerve activity.