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Am J Physiol Endocrinol Metab 275: E757-E762, 1998;
0193-1849/98 $5.00
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Vol. 275, Issue 5, E757-E762, November 1998

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

Davide Agnello1, Riccardo Bertini2, Silvano Sacco1, Cristina Meazza1, Pia Villa1,3, and Pietro Ghezzi1

1 "Mario Negri" Institute for Pharmacological Research, 20157 Milan; 2 Department of Pharmacology, Dompé SpA Research Center, 67100 L'Aquila; and 3 Consiglio Nazionale delle Ricerche-Cellular and Molecular Pharmacology Center, 20129 Milan, Italy

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 µg/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.

inflammation; cytokines; corticotropin-releasing factor; lipopolysaccharide; hypothalamus-pituitary-adrenal axis; interleukin-1; interleukin-6; Kupffer cells


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