John C D, Sahni V, Mehet D, Morris J F, Christian H C, Perretti M, Flower R J, Solito E, Buckingham J C
Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospital Campus, Du Cane Rd., London W12 0NN, UK.
FASEB J. 2007 Apr;21(4):1037-46. doi: 10.1096/fj.06-7299com. Epub 2007 Jan 11.
The N-formyl peptide receptors (FPRs) are a family of G-protein coupled receptors that respond to proinflammatory N-formylated bacterial peptides (e.g., formyl-Met-Leu-Phe, fMLF) and, thus, contribute to the host response to bacterial infection. Paradoxically, a growing body of evidence suggests that some members of this receptor family may also be targets for certain anti-inflammatory molecules, including annexin A1 (ANXA1), which is an important mediator of glucocorticoid (GC) action. To explore further the potential role of FPRs in mediating ANXA1 actions, we have focused on the pituitary gland, where ANXA1 has a well-defined role as a cell-cell mediator of the inhibitory effects of GCs on the secretion of corticotrophin (ACTH), and used molecular, genetic, and pharmacological approaches to address the question in well-established rodent models. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis identified mRNAs for four FPR family members in the mouse anterior pituitary gland, Fpr-rs1, Fpr-rs2, Fpr-rs6, and Fpr-rs7. Functional studies confirmed that, like dexamethasone, ANXA1 and two ANXA1-derived peptides (ANXA1(1-188) and ANXA1(Ac2-26)) inhibit the evoked release of ACTH from rodent anterior pituitary tissue in vitro. Fpr1 gene deletion failed to modify the pituitary responses to dexamethasone or ANXA1(Ac2-26). However, lipoxin A4 (LXA4, 0.02-2 microM, a lipid mediator with high affinity for Fpr-rs1) mimicked the inhibitory effects of ANXA1 on ACTH release as also did fMLF in high (1-100 microM) but not lower (10-100 nM) concentrations. Additionally, a nonselective FPR antagonist (Boc1, 100 microM) overcame the effects of dexamethasone, ANXA1(1-188), ANXA1(Ac2-26), fMLF, and LXA4 on ACTH release, although at a lower concentration (50 microM), it was without effect. Together, the results suggest that the actions of ANXA1 in the pituitary gland are independent of Fpr1 but may involve other FPR family members, in particular, Fpr-rs1 or a closely related receptor. They thus provide the first evidence for a role of the FPR family in the regulation of neuroendocrine function.
N-甲酰肽受体（FPRs）是一类G蛋白偶联受体，可对促炎性N-甲酰化细菌肽（如甲酰甲硫氨酸-亮氨酸-苯丙氨酸，fMLF）产生反应，从而参与宿主对细菌感染的反应。矛盾的是，越来越多的证据表明，该受体家族的某些成员也可能是某些抗炎分子的作用靶点，包括膜联蛋白A1（ANXA1），它是糖皮质激素（GC）作用的重要介质。为了进一步探索FPRs在介导ANXA1作用中的潜在作用，我们将重点放在垂体上，在垂体中，ANXA1作为GC对促肾上腺皮质激素（ACTH）分泌抑制作用的细胞间介质，其作用已明确，我们使用分子、遗传和药理学方法在成熟的啮齿动物模型中解决这个问题。逆转录聚合酶链反应（RT-PCR）分析在小鼠垂体前叶中鉴定出四种FPR家族成员的mRNA，即Fpr-rs1、Fpr-rs2、Fpr-rs6和Fpr-rs7。功能研究证实，与地塞米松一样，ANXA1和两种ANXA1衍生肽（ANXA1(1-188)和ANXA1(Ac2-26)）在体外可抑制啮齿动物垂体前叶组织中ACTH的诱发性释放。Fpr1基因缺失未能改变垂体对地塞米松或ANXA1(Ac2-26)的反应。然而，脂氧素A4（LXA4，0.02 - 2 microM，一种对Fpr-rs1具有高亲和力的脂质介质）模拟了ANXA1对ACTH释放的抑制作用，fMLF在高浓度（1 - 100 microM）而非低浓度（10 - 100 nM）时也有此作用。此外，一种非选择性FPR拮抗剂（Boc1，100 microM）可克服地塞米松、ANXA1(1-188)、ANXA1(Ac2-26)、fMLF和LXA4对ACTH释放的影响，尽管在较低浓度（50 microM）时它没有效果。总之，结果表明ANXA1在垂体中的作用独立于Fpr1，但可能涉及其他FPR家族成员，特别是Fpr-rs1或与之密切相关的受体。因此，它们为FPR家族在神经内分泌功能调节中的作用提供了首个证据。
