Sympathetic Nervous System Mediates Central Corticotropin-releasing Factor Induced Suppression of Natural Killer Cytotoxicity

Corticotropin-releasing factor (CRF) acts within the brain to elicit changes in neuroendocrine, autonomic and behavioral activity similar to those observed after stress. A reduction of cellular immune function as measured by splenic natural killer cell activity has also been described following the central administration of CRF. In this study we evaluated the role of the sympathetic nervous system in mediating CRF-induced suppression of natural killer (NK) cytotoxicity. Synthetic rat CRF (1.0 microgram) microinjected into the lateral ventricle increased noradrenergic function and reduced NK activity in the rat spleen. Pretreatment of the animals by chemical sympathectomy (6-hydroxy-dopamine, 100 mg/kg i.p. daily over 10 days) produced a greater than 95% reduction of splenic norepinephrine concentration and abolished completely both the CRF-induced increase in plasma catecholamine levels and the reduction in splenic NK activity. In addition, beta adrenergic receptor blockade (either propranolol, 10 mg/kg i.p., or butoxamine, 25 mg/kg i.p. 30 min before i.c.v. infusion) antagonized the CRF-induced reduction in NK activity. Measurement of circulating levels of adrenocorticotrophic hormone and corticosterone demonstrated that activation of the pituitary adrenal axis by CRF was dissociated from changes in NK activity. These findings suggest that the sympathetic nervous system mediates the suppression of splenic NK cytotoxicity after i.c.v. CRF.