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J Cell Physiol. 2007 Mar;210(3):774-83.

Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2.

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Department of Clinical Chemistry-Biochemistry, School of Medicine, University of Crete, Heraklion, Crete, Greece.


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 (CRF1) and CRF2 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-alpha) in LPS-activated macrophages, an effect peaking at 4 h. This effect did not involve changes on TNF-alpha transcription. (b) CRF peptide-induced suppression of TNF-alpha release depended on induction of COX-2 and PGE2 synthesis. (c) Use of specific CRF1 and CRF2 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-alpha production via enhancement of its transcription. In conclusion, this is the first report suggesting that CRF1 and CRF2 agonists exert a biphasic effect on macrophages. During the early stages of the inflammatory response, they suppress TNF-alpha release via induction of COX-2/PGE2 while later on they induce TNF-alpha transcription. Hence, the reported anti-inflammatory effect of CRF-peptides appears to involve macrophages and is confined at the early stage of inflammation.

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