Evidence from immunoneutralization and antisense studies that the inhibitory actions of glucocorticoids on growth hormone release in vitro require annexin 1 (lipocortin 1)

Abstract

1 Our previous studies have identi®ed a role for annexin 1 as a mediator of glucocorticoid action in the neuroendocrine system. The present study centred on growth hormone (GH) and exploited antisense and immunoneutralization strategies to examine in vitro the potential role of annexin 1 in e ecting the regulatory actions of glucocorticoids on the secretion of this pituitary hormone. 2 Rat anterior pituitary tissue responded in vitro to growth hormone releasing hormone, forskolin, 8-Bromo-cyclic adenosine 3'5'-monophosphate (8-Br-cyclic AMP) and an L-Ca 2+ channel opener (BAY K8644) with concentration-dependent increases GH release which were readily inhibited by corticosterone and dexamethasone. 3 The inhibitory actions of the steroids on GH release elicited by the above secretagogues were e ectively reversed by an annexin 1 antisense oligodeoxynucleotide (ODN), but not by control (sense or scrambled) ODNs, as also were the glucocorticoid-induced increases in annexin 1. Similarly, a speci®c anti-annexin 1 monoclonal antibody quenched the corticosterone-induced suppression of secretagogue-evoked GH release while an isotype matched control antibody was without e ect. 4 Transmission electron micrographs showed that the integrity and ultrastructural morphology of the pituitary cells were well preserved at the end of the incubation and una ected by exposure to the ODNs, antibodies, steroids or secretagogues. 5 The results provide novel evidence for a role for annexin 1 as a mediator of the inhibitory actions of glucocorticoids on the secretion of GH by the anterior pituitary gland and suggest that its actions are e ected at a point distal to the formation of cyclic AMP and Ca 2+ entry.

Opposing influences of glucocorticoids and interleukin‐1β on the secretion of growth hormone and ACTH in the rat in vivo: role of hypothalamic annexin 1

“…Thus, results from clinical studies suggest that acute GC administration causes a transient increase GHRH secretion (Fernandez-Vazquez et al, 1995) and/or depresses the secretion of somatostatin (Muruais et al, 1991). By contrast, over the same timeframe GCs exert an inhibitory in¯uence on the somatotrophs and thereby suppress GHRH-stimulated GH release (Vale et al, 1983;Ceda et al, 1987;Taylor et al, 2000a). The present study provides no further insight to the locus of corticosterone/annexin 1 action within the hypothalamus although the magnitude of the changes in serum GH suggests that alterations in both GHRH and somatostatin secretion may be involved.…”

“…The mechanism by which the GCs evoke this secretory response is unclear. Casanueva et al (1990) argued against an action at the pituitary level, a view which is supported by observations that, in stark contrast to their longer term actions, GCs inhibit GHRH-induced GH release from rodent pituitary tissue in vitro within this short timeframe (Vale et al, 1983;Ceda et al, 1987;Taylor et al, 2000a). Other data favour a transient action at the hypothalamic level which augments GHRH release (Fernandez-Vazquez et al, 1995) and/or depresses the secretion of somatostatin (Muruais et al, 1991).…”

An annexin 1 (ANXA1)‐derived peptide inhibits prototype antigen‐driven human T cell Th1 and Th2 responses in vitro

“…Previously published binding studies with ANXA1 similarly suggest the existence of specific surface receptors on peripheral blood leucocytes [20,21,28], while a more recent study implicates a member of the FMLP receptor family as a candidate receptor for Ac2–26 [23]. The observation that the anti‐inflammatory activities of ANXA1 can be abrogated both in vitro and in vivo by anti‐ANXA1 neutralizing antibodies [30–32] further suggests the existence of one or more cell surface receptors for ANXA1. Together, these observations support the hypothesis that ANXA1 acts in an autocrine or paracrine fashion on cells such as monocytes, which may both secrete ANXA1 and bind it extracellularly.…”

“…It appears to depend on externalization of the protein and its interaction with one or more binding proteins [20–22], which in some cells also bind FMLP [23]. Expression and externalization of ANXA1 are induced in some, but not all cell types by glucocorticoids [14,24–29], and there is evidence that it may mediate certain of the anti‐inflammatory effects of glucocorticoids in some animal models [14,30–32]. In addition, other stimuli, including IL‐6 [33] and lipopolysaccharide [34] may induce ANXA1 expression and externalization.…”

Folliculo-stellate Cells: Paracrine Communicators in the Anterior Pituitary

“…Most of the endocrine cells contain glucocorticoid receptors and so are subject to transcriptional inhibition by glucocorticoids, but lactotrophs apparently do not [73] and all are subject to the early delayed glucocorticoid-induced inhibition that requires Anx A1 as demonstrated by the blocking effects of both antibodies and antisense [92,93]. F-S cells make functional contacts with all the classical endocrine cell types in proportion to their number and the Anx A1 that they export can therefore exert the early-delayed feedback on secretion of all adenohypophyseal hormones.…”