Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-α release from macrophages via induction of COX-2 and PGE2
✍ Scribed by Christos Tsatsanis; Ariadne Androulidaki; Erini Dermitzaki; Achille Gravanis; Andrew N. Margioris
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 369 KB
- Volume
- 210
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Corticotropin‐releasing factor (CRF), the principal regulator of the hypothalamus‐pituitary‐adrenal (HPA) axis, also modulates the inflammatory response directly, via its effect on mast cells and macrophages. On macrophages, it augments production of lipopolysaccharide (LPS)‐induced pro‐inflammatory cytokines. CRF and its related peptides may also act as anti‐inflammatory agents. Aim of the present work was to examine the role of macrophages on the anti‐inflammatory effects of CRF‐peptides and the mechanism involved. Thus, we examined if CRF receptor 1 (CRF~1~) and CRF~2~ agonists exert any anti‐inflammatory effect on primary mouse macrophages. We have found that: (a) CRF, Urocortin (UCN)1 and UCN2 transiently suppressed the release of Tumor Necrosis Factor‐alpha (TNF‐α) in LPS‐activated macrophages, an effect peaking at 4 h. This effect did not involve changes on TNF‐α transcription. (b) CRF peptide‐induced suppression of TNF‐α release depended on induction of COX‐2 and PGE2 synthesis. (c) Use of specific CRF~1~ and CRF~2~ antagonists suggested that this effect involved both CRF receptor types. (d) The effect of CRF‐peptides on COX‐2 was mediated via PI3K and p38MAPK. (e) Longer exposure of macrophages to CRF‐peptides resulted in induction of TNF‐α production via enhancement of its transcription. In conclusion, this is the first report suggesting that CRF~1~ and CRF~2~ agonists exert a biphasic effect on macrophages. During the early stages of the inflammatory response, they suppress TNF‐α release via induction of COX‐2/PGE2 while later on they induce TNF‐α transcription. Hence, the reported anti‐inflammatory effect of CRF‐peptides appears to involve macrophages and is confined at the early stage of inflammation. J. Cell. Physiol. 210: 774–783, 2007. © 2006 Wiley‐Liss, Inc.