ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P224

Negotiating with a pea-sized hormone factory: the mediatory role of pituitary formyl peptide receptor (FPR) ligands in times of stress

Vance Naughton1, Bradley Spencer-Dene2, Chris John1 & Julia Buckingham1

1Imperial College London, London, UK; 2London Resarch Institute, London, UK.

Pituitary folliculo-stellate cells express annexin-A1 (ANXA1), a mediator protein necessary for glucocorticoid(GC)-induced negative feedback of adreno-corticotrophic hormone (ACTH) release. ANXA1 acts via formyl peptide receptors (FPR in man, Fpr in rodents). Whilst pituitary tissue does not express Fpr1, functional data suggested Fpr2/Fpr3-selective ligands mediate feedback-like inhibition of ACTH.

Hypothesis: Fpr2-selective ligands inhibit secretagogue-induced ACTH release from pituitary tissue in vitro.

Methods: Firstly, we cultured anterior pituitary cells from Sprague–Dawley rats (n=12, male, 200–220 g) in CRH-stimulated (100 nmol/l) or basal conditions, along with peptide agonists for Fpr2 (WKYMVm (10−10, 10−9, 10−8, 10−7, 10−6 mol/l) and F2L (50, 100, 200, 400, 800 nmol/l)) or Fpr1 (fMLF (10−9, 10−8, 10−7, 10−6, 10−5 mol/l)). ACTH was measured by RIA after 4 h and data (mean±S.E.M.) analysed by two-way ANOVA. Secondly, the pituitary Fpr2/3 distribution was determined by immuno-fluorescent detection of pituitary cell subtypes and green fluorescent protein (GFP) in sections of Fpr2/3-null/GFP-positive mice (n=4, male).

Results: Concordant with previous data, low dose fMLF did not affect ACTH release, confirming Fpr1 is not instrumental in ACTH regulation. Surprisingly, in separate experiments, two-way ANOVA revealed a significant stimulatory effect of WKYMVm and F2L on ACTH release (F(7,176)=71.38 and 49.17 respectively; P<0.0001). ACTH release from CRH-stimulated, WKYMVm-treated (10−9 mol/l) and CRH-stimulated, F2L-treated cells (800 nmol/l) versus CRH control was 20% (1680 pg/ml±111 vs 1320 pg/ml±75) and 60% (2953 pg/ml±188 vs 1817 pg/ml±227) higher, respectively (P<0.05). GFP as a proxy for Fpr2/3, was evident in corticotrophs, somatotrophs, and lactotrophs, but, importantly, not in folliculo-stellates (anti-S100b).

Conclusion: Our work shows rodent Fpr2-selective ligands stimulate ACTH release and suggests Fpr2 does not mediate feedback-like regulation of pituitary ACTH release. Ongoing work will determine whether inhibition of ACTH is mediated by Fpr3 ligands, namely, 15-epi lipoxin A4.

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