CORTICOTROPIN-RELEASING HORMONE IS INVOLVED IN CONDITIONED STIMULUS-INDUCED REDUCTION OF NATURAL-KILLER-CELL ACTIVITY BUT NOT IN CONDITIONED ALTERATIONS IN CYTOKINE PRODUCTION OR PROLIFERATION RESPONSES

Research from our laboratory has demonstrated that the presentation of an aversive conditioned stimulus produces pronounced suppression of s everal in vitro measures of immune status. The present study was desig ned to evaluate the role of central corticotropin-releasing hormone (C RH) in the mechanisms mediating these conditioned effects. The aversiv e conditioned stimulus was a distinct environment that had previously been associated with electric footshock. Lewis rats received intravent ricular administration of either buffered saline or a dose of the CRH- selective receptor antagonist alpha-helical CRH((9-41)) (0, 0.5, 5, or 50 mu g) prior to exposure to the aversive conditioned stimulus or ho me cage control treatment. The aversive conditioned stimulus produced decreases in splenic natural killer cell activity, splenocyte responsi veness to the mitogens concanavalin A (ConA), phytohemagglutinin (PHA) , lipopolysaccharide (LPS), and the combination of ionomycin and phorb ol myristate acetate (PMA), blood leukocyte responsiveness to ConA and PHA, and the production of interleukin-2 and interferon-gamma by acti vated splenocytes. The conditioned stimulus also produced an increase in plasma levels of corticosterone. Pretreatment with alpha-helical CR H((9-41)) completely blocked the conditioned stimulus-induced suppress ion of natural killer cell. activity. The CRH antagonist had no attenu ative effect on the conditioned suppression of splenocyte or blood leu kocyte proliferation in response to mitogens, or the production of int erleukin-2 or interferon-gamma by activated splenocytes. There was als o no effect of alpha-helical CRH((9-41)) on the conditioned stimulus-i nduced increase in plasma corticosterone. These findings suggest that conditioned stimulus-induced suppression of natural killer cell activi ty is mediated by a mechanism that involves activity at central CRH re ceptors, and that this conditioned modulation is independent of HPA ac tivation. Furthermore, these results indicate that the mechanisms invo lved in conditioned stimulus-induced suppression of proliferative or c ytokine production responses are distinct from those involved in the m odulation of natural killer cell activity.