PSYCHOSOCIAL STRESS-INDUCED FEVER--ROLE OF CYTOKINES

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Exposure to psychosocial stress produces rises in body temperature of as much as 2 degrees Celsius in rats. Rises in body temperature of people in response to psychological stress have also been reported. Psychosocial stress has also been shown to alter the course of AIDS. Over the past several years we have generated data that support the hypothesis that stress "hyperthermia" is actually a fever (i.e., an elevation in thermoregulatory set-point), caused by endogenous pyrogens and prostaglandin E2. In addition, we have shown that simply exposing a rat to a novel environment results in a significant increase in the plasma concentration of IL-6, a mediator of inflammation and immunity, and that pretreatment of rats with antiserum to TNF (i.e., TNFalpha) results in an increase in stress-fevers. The hypothesis we are interested in testing is that cytokines and other peptides thought to be involved in infection- induced fever (both in inducing fever and modulating the magnitude of the fever) (e.g., IL-1, TNF, IL-6, PGE2 arginine vasopressin (AVP) and alpha- MSH) are responsible for that portion of stress-induced hyperthermia that is not caused by endogenous opioids. The specific aims of the proposed studies are as follows: 1. To continue our investigations on the effects of exposure to a novel environment (in rats) on plasma activity of IL-6, PGE2, arginine vasopressin, and alpha-MSH. 2. To determine whether plasma activities of IL-6, IL-1, TNF, PGE2, AVP, and alpha-MSH are high enough to affect (either increases or decreases) the stress-induced rise in temperature. 3. To test the hypothesis that psychological stress induces the release of IL-1, TNF, IL-6, PGE2, AVP, and alpha-MSH into the cerebrospinal fluid, or brain tissue of rats. 4. To test the hypothesis that psychological stress induces the spontaneous release of IL-1, TNF, or IL-6 from Kupffer cells or circulating blood monocytes isolated following the stress. 5. To test the hypothesis that psychological stress makes Kupffer cells or circulating blood monocytes more sensitive to other stimuli, such as lipopolysaccharide, known to cause the synthesis and release of IL-1, TNF, and IL-6. 6. To test the hypothesis that pretreatment of rats with antibodies or specific receptor antagonists against IL-1, TNF, IL-6, AVP, and alpha-MSH alters (either increases or decreases) stress-induced hyperthermia. These studies may have relevance for understanding the progression of AIDS from latent HIV infection to full-blown disease since studies from another laboratory have shown that IL-6 and TNF results in a synergistic induction of HIV expression in chronically HIV-infected cell models.