title: 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.
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 (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.
authors.affiliation: Department of Clinical Chemistry-Biochemistry, School of Medicine, University of Crete, Heraklion, Crete, Greece. tsatsani@med.uoc.gr
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Ariadne
authors.initials: A
authors.lastname: Androulidaki
authors.forename: Erini
authors.initials: E
authors.lastname: Dermitzaki
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Margioris
mesh_terms: D000818:Animals; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054832:Urocortins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D008070:Lipopolysaccharides; D018019:Receptors, Corticotropin-Releasing Hormone; D014409:Tumor Necrosis Factor-alpha; D054832:Urocortins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone