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

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.

Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

“…Overall, some NF-IL6-IR in pituitary cells was clearly detected in co-localization with STAT3/NFκB but also without such a co-localization. Novel environment stress did not significantly induce STAT3 or NFκB-IR in the brain (data not shown), although this had previously been reported to be the case after foot shock for STAT3 [31] or restraint stress for NFκB [30]. This most likely was due to the much more moderate stress response to a novel environment in the present study.…”

“…Previously, the inflammatory transcription factors STAT3 and NFκB have been implicated in HPA-axis activation [30,31,41,42,45,46]. Moreover, STAT3, NFκB, and NF-IL6 have been implicated in proopiomelanocortin (POMC, precursor of ACTH) and CRH-expression [45-48].…”

“…Recently, NFκB, which is also activated by TNFα, was reported to be crucial for the stress response after LPS and open field stress in vivo [30]. While LPS-induced NFκB activity increased IL-6-expression in folliculostellate cells, it inhibited ACTH expression in corticotropes.…”

“…Whether activation of inflammatory transcription factors also occurs during psychological stress has been previously investigated for STAT3 and NFκB [30,31] but remains unknown for NF-IL6.…”

Targeting the annexin 1‐formyl peptide receptor 2/ALX pathway affords protection against bacterial LPS‐induced pathologic changes in the murine adrenal cortex

“…As discussed earlier, the initial steroidogenic response to LPS is affected by increased secretion of ACTH (16) and by direct action of LPS and proinflammatory cytokines (53, 54) within the adrenal cortex. Several mechanisms may contribute to the subsequent potentially harmful effects of the toxin on the adrenal cells, which lead to a failure of steroidogenesis.…”