Modulation of endothelial prostaglandin synthesis by corticotropin releasing factor and antagonists.
Corticotropin releasing factor (CRF) is a hypothalamic hormone that also displays autocrine/paracrine roles at peripheral sites. High concentrations of CRF have been identified in endothelial cells and other inflammatory tissues. We investigated the effects of CRF and antagonists in the regulation of prostaglandin synthesis in bovine aortic endothelial cells, and also characterized the binding of CRF in these cells. Interleukin-1alpha increased prostacyclin (prostaglandin I2) synthesis in endothelial cells and this response to interleukin-1alpha was abolished by simultaneous exposure to CRF. The effect of CRF on interleukin-1alpha-induced prostaglandin synthesis was antagonised by the CRF receptor antagonist alpha-helical CRF-(9-41). In addition, this as well as another CRF receptor antagonist, namely [D-Phe12]CRF-(12-41), when applied alone at low concentrations inhibited the interleukin-1alpha-induced prostaglandin synthesis similarly to CRF, suggesting partial agonistic action. Binding of [125I]-labeled CRF in endothelial cells was saturable and fitted a two sites model. Kd for the higher-affinity class of receptors was 0.2 +/- 0.02 nM, and Bmax 0.79 +/- 0.095 fmol/mg protein. The lower-affinity class of receptors had a Kd of 1.77 +/- 0.14 microM and Bmax 0.97 +/- 0.12 fmol/mg protein. These findings suggest a direct role for CRF in the local regulation of inflammation.
Fleisher-Berkovich
S
S
Department of Clinical Pharmacology, Corob Center for Health Sciences, Ben-Gurion University and Soroka Medical Center, Beer-Sheva, Israel.
Rimon
G
G
Danon
A
A
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors
D007375:Interleukin-1; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; D011464:Epoprostenol