title: Evidence from in vitro and in vivo studies showing that nuclear factor-κB within the pituitary folliculostellate cells and corticotrophs regulates adrenocorticotrophic hormone secretion in experimental endotoxaemia.
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.
authors.affiliation: Department of Medicine, Imperial College London, Hammersmith Campus, London, UK.
authors.forename: D K
authors.initials: DK
authors.lastname: Mehet
authors.forename: J
authors.initials: J
authors.lastname: Philip
authors.forename: E
authors.initials: E
authors.lastname: Solito
authors.forename: J C
authors.initials: JC
authors.lastname: Buckingham
authors.forename: C D
authors.initials: CD
authors.lastname: John
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D052680:Corticotrophs / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology*; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone