ROLES OF SYMPATHETIC NERVOUS-SYSTEM IN THE SUPPRESSION OF CYTOTOXICITY OF SPLENIC NATURAL-KILLER-CELLS IN THE RAT

1. We previously demonstrated that a central injection of interferon-a lpha in rats induced a suppression of cytotoxicity of splenic natural killer cells which depended upon intact splenic sympathetic innervatio n, suggesting the important role of the splenic nerve in immunosuppres sion, To further study the mechanisms of this phenomenon, we investiga ted: (1) the effects of a central injection of recombinant human inter feron-alpha on the electrical activity of the splenic nerve, and (2) t he responses of splenic natural killer cytotoxicity on the electrical stimulation of the splenic nerve in urethane with alpha-chloralose ana esthetized rats. 2. An injection of recombinant human interferon-a (1. 5 x 10(3) and 6.0 x 10(3) units (u) per rat) into the third cerebral v entricle produced a sustained and long lasting (at least for more than 60 min) increase in the electrical activity of splenic sympathetic ne rve filaments in a dose-dependent manner. Following an intra-third-ven tricular injection of recombinant human interferon-a at a dose of 6.0 x 10(3) u, the efferent discharges were elevated 2-6 times that of the pre-injection level with a mean onset latency of 12 min (8-16 min). N o changes in the arterial blood pressure and body temperature were obs erved after injections of recombinant human interferon-alpha. 3. The e xcitation of the nerve activity induced by intra-ventricular recombina nt human interferon-alpha was reversibly suppressed by an intravenous injection of an opioid antagonist, naloxone (1 mg/kg in 0.1 ml saline) , whereas the injection of naloxone alone did not affect either the ba seline level of the nerve activity or the systemic blood pressure. 4. The cytotoxicity of natural killer cells in the spleen measured by a s tandard chromium release assay was reduced 20 min after the laparotomy alone in anaesthetized rats. The reduced natural killer activity then recovered significantly when the splenic nerve was cut immediately af ter the laparotomy. When the peripheral cut end of the splenic nerve w as subsequently stimulated (0.5 mA, 0.5 ms, 20 Hz for 20 min), a furth er suppression of natural killer cytotoxicity was observed. 5. The red uction of natural killer cytotoxicity produced by the stimulation of t he splenic nerve was completely blocked by an intravenous injection of nadolol (a peripherally acting beta-adrenergic receptor antagonist), but not by that of prazosin (an alpha-antagonist). 6. These results in dicate that a central injection of recombinant human interferon-alpha activates the splenic sympathetic nerve through brain opioid receptors and thereby suppresses the natural killer cytotoxicity by beta-adrene rgic mechanisms. It is suggested that the splenic sympathetic nerve ma y thus be one of the important pathways by which the brain modulates p eripheral cellular immunity.