CORTICOSTEROID-INDEPENDENT INHIBITION OF TUMOR-NECROSIS-FACTOR PRODUCTION BY THE NEUROPEPTIDE UROCORTIN

Urocortin (UCN) is a neuropeptide homologous with corticotropin-releas ing factor (CRF), which has anti-inflammatory activities not all media ted by corticosteroids. In mice, UCN (1 mu g/mouse sc) significantly r educed lipopolysaccharide (LPS)-induced serum tumor necrosis factor (T NF) and interleukin (IL)-1 beta levels in vivo but did not affect seru m IL-6. These effects were paralleled by a rise in corticosterone (CS) levels. Blockade of the CS increase by cyanoketone did not prevent TN F inhibition by UCN, suggesting the neuropeptide has anti-inflammatory mechanisms independent of the hypothalamus-pituitary-adrenal axis. In fact UCN had a direct inhibitory effect on LPS-induced TNF in rat Kup ffer cells at concentrations between 10(-10) and 10(-16) M, and this e ffect was related to increased cAMP levels. However, the in vivo inhib ition of LPS-induced IL-1 beta by UCN was reversed by cyanoketone, ind icating that the increase of endogenous glucocorticoids might be more important in IL-1 beta inhibition than in TNF inhibition by UCN.