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. Tn addi tion, numerous studies support autocrine/paracrine roles for this pept ide at peripheral sites. CRF and CRF binding sites have been identifie d in different regions of the central nervous system as well as in the heart, spleen, adrenal and testis, and high levels of CRF were detect ed in inflamed fibroblasts. However, the precise physiological or path ophysiological role of peripheral CRF cannot yet be discerned. Here we show that CRF, through interaction with specific membrane receptors, blocks the interleukin-1 alpha (IL-1 alpha)-stimulated prostaglandin ( PG) synthesis in fibroblasts. Binding of [I-125]-labeled CRF in fibrob lasts was saturable and fitted a two sites model. K-D for the higher-a ffinity class of receptors was 20+/-2.2 pM, and B-max 1.95+/-0.22 fmol /mg protein. For the lower-affinity class of receptors K-D was 160+/-1 7 nM, and B-max 2.38+/-0.27 fmol/mg protein. CRF blocked the effect of IL-1 alpha on PGE(2) synthesis, and this was antagonised by D-PheCRF( 12-41). In addition, the CRF receptor antagonists alpha helical CRF9-4 1 and D-PheCRF(12-41) at high concentrations inhibited the IL-1 alpha- induced PG synthesis similarly to CRF, suggesting partial agonistic ac tion. Taken together, these results suggest a modulatory role of CRF i n inflammation. (C) 1998 Elsevier Science B.V. All rights reserved.