Corticotropin releasing factor modulates interleukin-1-induced prostaglandin synthesis in fibroblasts: receptor binding and effects of antagonists.
Corticotropin releasing factor (CRF) is a predominant regulator of the neuroendocrine, autonomic and behavioral responses to stress. In addition, numerous studies support autocrine/paracrine roles for this peptide at peripheral sites. CRF and CRF binding sites have been identified in different regions of the central nervous system as well as in the heart, spleen, adrenal and testis, and high levels of CRF were detected in inflamed fibroblasts. However, the precise physiological or pathophysiological role of peripheral CRF cannot yet be discerned. Here we show that CRF, through interaction with specific membrane receptors, blocks the interleukin-1alpha (IL-1alpha)-stimulated prostaglandin (PG) synthesis in fibroblasts. Binding of [125I]-labeled CRF in fibroblasts was saturable and fitted a two sites model. K(D) for the higher-affinity class of receptors was 20+/-2.2 pM, and Bmax 1.95+/-0.22 fmol/mg protein. For the lower-affinity class of receptors K(D) was 160+/-17 nM, and Bmax 2.38+/-0.27 fmol/mg protein. CRF blocked the effect of IL-1alpha on PGE2 synthesis, and this was antagonised by D-PheCRF12-41. In addition, the CRF receptor antagonists alpha helical CRF9-41 and D-PheCRF12-41 at high concentrations inhibited the IL-1alpha-induced PG synthesis similarly to CRF, suggesting partial agonistic action. Taken together, these results suggest a modulatory role of CRF in 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
D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D005347:Fibroblasts; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*
C083591:H-R corticotropin-releasing factor (12-41), Phe(12)-Nle(21,38), C(alpha-MeLeu(37))-; D007375:Interleukin-1; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C113202:phenylalanyl corticotropin-releasing factor (12-41); D003346:Corticotropin-Releasing Hormone; D015232:Dinoprostone