MULTIPLE MECHANISMS MEDIATE ANTIPYRETIC ACTION OF GLUCOCORTICOIDS

Glucocorticoids inhibit various components of the acute phase response , particularly the increase in body temperature (fever) induced by a v ariety of stimuli. In the present study these observations have been e xtended, and we have determined the effect of glucocorticoid treatment or surgical adrenalectomy on the cytokine and prostaglandin (PG) conc entrations in plasma and cerebrospinal fluid (CSF) during the febrile response to endotoxin. Dexamethasone treatment, either before or after endotoxin injection, markedly inhibited fever and the increased plasm a interleukin (IL)-6 and CSF IL-6, PGE(2), and PGF(2 alpha) concentrat ions. Adrenalectomized (ADX) rats showed higher fevers and plasma and CSF IL-6, PGE(2), and PGF(2 alpha), concentrations compared with sham- operated animals and exhibited a lower plasma-to-CSF IL-6 ratio than s ham-operated animals. Dexamethasone pretreatment also inhibited fever induced by centrally injected TNF-alpha, IL-1 beta, or IL-6. Pyrogenic response to IL-8 was not modified by indomethacin but was markedly in hibited by prior treatment with dexamethasone. These results support t he hypothesis that endogenous glucocorticoids function as part of an i nhibitory feedback system involved in the modulation of fever and that multiple mechanisms may be involved in their antipyretic effect.