blockade demonstrated a significant activation of the pituitary-adrenal axis, whereas only treatment with CRF alone suppressed NK activity. Additional experiments have further suggested that the increased secretion of glucocorticoids does not significantly contribute to CRF suppression of NK cytotoxicity. Intraventricular CRF administered to animals in whom synthesis of corticosterone was blocked pharmacologically by preadministering metyrapone and aminoglutethimide before CRF infusion showed a reduction of NK activity comparable to that in animals who had not undergone similar blockade of glucocorticoid synthesis. Together these data suggest that the immunosuppressive effect of central CRF is dissociated from the activation of the pituitary-adrenal axis.
These data, evaluating the role of the autonomic nervous system and neuroendocrine systems in mediating the effects of CRF, demonstrated that the autonomic nervous system is a salient efferent pathway by which CRF suppresses NK activity; blockade of this outflow completely antagonized the action of CRF. Second, CRF immunosuppression appeared independent of the activation of the pituitary gland. Significant increases of plasma levels of these hormones occurred without necessarily reducing NK activity.
Clinical studies have clarified that a reduction of immune function is associated with psychological processes in persons undergoing severe, adverse life events. In addition, reduced NK activity is correlated with the severity of depressive symptoms in both stressed persons and depressed patients. Based on our interest in understanding the link between the central nervous system and immune function, our clinical research has been extended to an animal model that involves the central administration of CRF. Intraventricular CRF has been found to reduce NK activity in addition to its abilities to coordinate a pattern of behavioral, pituitary, and autonomic responses similar to those found in animals exposed to some types of stressors. Central action of CRF, together with the finding that ganglionic blockade completely antagonizes the suppression of NK activity induced by CRF, provide direct evidence that changes in the brain are communicated to NK cells via the autonomic nervous system.
This work was partly supported by NIMH grants #MH44275-01, MH30914, the San Diego VA Clinical Research Center on Alcoholism, and a VA Merit Review.