Interferon-alpha acts at the preoptic hypothalamus to reduce natural killer cytotoxicity in rats

Abstract

We previously demonstrated that an intracerebroventricular injection of recombinant human interferon-alpha (rhIFN-alpha) reduced the cytotoxicity of splenic natural killer (NK) cells in rats and mice. In the present study, we investigated the brain sites at which rhIFN-alpha acts to suppress splenic NK activity in unanesthetized rats implanted unilaterally with a chronic hypothalamic cannula. A microinjection of 200 U of rhIFN-alpha into the medial part of the preoptic hypothalamus reduced NK activity to approximately 60% of control 30 min after the injection. Administration of 50 U of rhIFN-alpha also decreased NK activity to approximately 80%. The injection of 200 U of rhIFN-alpha into other hypothalamic areas (lateral preoptic hypothalamus, ventromedial hypothalamus, lateral hypothalamus, and paraventricular nucleus) had no effect. The medial preoptic hypothalamus-rhIFN-alpha-induced immunosuppression was completely blocked by splenic denervation, but not by adrenalectomy. These results suggest that IFN-alpha suppresses splenic NK activity predominantly through the medial preoptic hypothalamus-sympathetic pathway.

Central IL-1 differentially regulates peripheral IL-6 and TNF synthesis

“…For example, Sundar et al [13] reported that central IL-1 produced a marked reduction of peripheral lymphocyte activities, and that the suppressive effect was attenuated after ganglionic blockade. Similarly, the suppressive effects of foot-shock stress [22], intracranial administration of interferon-h [23], and hypothalamic stimulation [24] on splenic lymphocytes and natural killer cells are also known to be mediated through sympathetic activation. Our results are similar to these observations in that the peripheral IL-6 response induced by brain IL-1 was much depressed by ganglionic blockade, indicating a significant role for the autonomic nervous system in the response.…”

Neuroimmunomodulatory Actions of Hypothalamic Interferon-α

“…Again, the reduced NK cytotoxicity was abolished by pretreatment with NLTX. Furthermore, we found that the most sensitive site to microinjected IFN-· for reducing the splenic NK cytotoxicity was located in the MPO [40]. The injection of rhIFN-· at 50 and 200 U into the MPO decreased the splenic NK cytotoxicity to about 77 and 59% of the preinjection level, but no changes in NK cytotoxicity were observed after injection of rhIFN-· (200 U) into the ventromedial hypothalamus, the lateral preoptic area, the lateral hypothalamus and the paraventricular nucleus (PVN).…”

“…We focused our attention to the hypothalamo-pituitary-adrenocortical axis and the splenic innervation as potential pathways to mediate the central messages evoked by the IFN-·-CRF system. The adrenalectomy did not influence the immunosuppression after injection of rhIFN-· either into the cerebral ventricle or the MPO in the rat [27,40], suggesting that adrenal hormones do not play major roles in this immunosuppression. In fact, the main effect of IFN-· on the hypothalamo-pituitary-adrenocortical axis seems to be inhibitory [29].…”

“…On the other hand, splenic denervation completely abolished the reduced NK cytotoxicity [27,40]. Since the splenic nerve consists mainly of sympathetic fibers [43], it is suggested that the sympathetic nerve innervating the spleen is involved in mediating cytotoxicity.…”

Possible involvement of brain cytokines and 5-HT system in chronic fatigue syndrome

“…We have shown that the central, but not peripheral, administration of IFN-a produces a significant suppression of splenic NK cell activity through the activation of the splenic sympathetic nerve in rats [15,16]. In addition, the action site of IFN-a to induce suppression of NK activity was the MPO [17,18], where expression of IFN-a mRNA increased on day 7 after poly I:C. It has been reported that IFN-a, but not IL-1h and TNF-a, is elevated in cerebrospinal fluid in patients with CFS [19]. Thirdly, brain 5-HT, which is suggested to be involved in the central mechanisms of the exercise-induced fatigue [9], decreased in the prefrontal cortex probably due to the IFN-a-induced over-expression of 5-HTT.…”