Corticosteroid-independent inhibition of tumor necrosis factor production by the neuropeptide urocortin

Urocortin (UCN) is a neuropeptide homologous with corticotropin-releasing factor (CRF), which has anti-inflammatory activities not all mediated by corticosteroids. In mice, UCN (1 microg/mouse sc) significantly reduced lipopolysaccharide (LPS)-induced serum tumor necrosis factor (TNF) and interleukin (IL)-1beta levels in vivo but did not affect serum IL-6. These effects were paralleled by a rise in corticosterone (CS) levels. Blockade of the CS increase by cyanoketone did not prevent TNF 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 Kupffer cells at concentrations between 10(-10) and 10(-16) M, and this effect was related to increased cAMP levels. However, the in vivo inhibition of LPS-induced IL-1beta by UCN was reversed by cyanoketone, indicating that the increase of endogenous glucocorticoids might be more important in IL-1beta inhibition than in TNF inhibition by UCN.