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Evidence From In Vitro and In Vivo Studies Showing that Nuclear Factor-Kappa B Within the Pituitary Folliculostellate Cells and Corticotrophs Regulates Adrenocorticotrophic Hormone Secretion in Experimental Endotoxaemia

Authors


Dr C. D. John, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Commonwealth Building, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK (e-mail: c.john@imperial.ac.uk).

Abstract

The hypothalamic-pituitary-adrenocortical (HPA) responses to bacterial infection are mediated, in part, by the actions of lipopolysaccharide (LPS) on pituitary folliculostellate (FS) cells that release pro-inflammatory cytokines [e.g. interleukin (IL)-6] and thereby facilitate adrenocorticotrophic hormone (ACTH) release from neighbouring corticotrophs. In the present study, two murine pituitary cell lines [TtT/GF (FS cells) and AtT20 D16:16 (corticotrophs)], alone and in co-culture, and an in vivo model of endotoxaemia were used to examine the potential role of nuclear factor-kappa B (NF-κB) in mediating LPS-induced ACTH secretion. Both cell lines expressed mRNAs for the key components of the LPS signalling system. LPS stimulated IL-6 release from TtT/GF cells via a glucocorticoid-sensitive, NF-κB-dependent mechanism; it also activated NF-κB in AtT20 cells, as did corticotrophin-releasing hormone (CRH). IL-6 potentiated (but LPS reduced) the stimulatory effects of CRH on ACTH release from AtT20 cells, whereas blockade of NF-κB (SC-514) increased the ACTH release induced by CRH in the presence or absence of LPS. In co-cultures, CRH and LPS acted synergistically to induce release of both IL-6 and ACTH. However, although SC-514 suppressed the release of IL-6 evoked by CRH and LPS, it potentiated the concomitant increase in ACTH release. In vivo both immunological (LPS) and psychological (restraint) stress increased intrapituitary NF-κB, whereas an NF-κB inhibitor (PHA781535E) attenuated the LPS-induced release of ACTH and abolished the HPA response to restraint stress. The results obtained in the present study support the premise that NF-κB plays an important role in mediating LPS signalling in the anterior pituitary gland, particularly in relation to IL-6 and ACTH secretion, and provide novel evidence that NF-κB blockade in vivo compromises stress-induced ACTH release.

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