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.
Agnello
D
D
"Mario Negri" Institute for Pharmacological Research, 20157 Milan, Italy.
Bertini
R
R
Sacco
S
S
Meazza
C
C
Villa
P
P
Ghezzi
P
P
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D003489:Cyanoketone / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D007700:Kinetics; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D054832:Urocortins
D000305:Adrenal Cortex Hormones; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D054832:Urocortins; D003489:Cyanoketone; D003346:Corticotropin-Releasing Hormone