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

Abstract

This study exploited established immunoneutralization protocols and an N‐terminal annexin 1 peptide (annexin 1Ac2 – 26) to advance our knowledge of the role of annexin 1 as a mediator of acute glucocorticoid action in the rat neuroendocrine system in vivo. Rats were treated with corticosterone (500 μg kg−1, i.p.) or annexin 1Ac2 – 26 (0.1 – 10 ng rat−1, i.c.v.) and 75 min later with interleukin 1β (IL‐1β, 10 ng rat−1, i.c.v. or 500 μg kg−1, i.p). Blood was collected 1 h later for hormone immunoassay. Where appropriate, anti‐annexin 1 polyclonal antiserum (pAb) was administered subcutaneously or centrally prior to the steroid challenge. Corticosterone did not affect the resting plasma corticotrophin (ACTH) concentration but suppressed the hypersecretion of ACTH induced by IL‐1β (i.p. or i.c.v.). Its actions were quenched by anti‐annexin 1 pAb (s.c. or i.c.v) and mimicked by annexin 1Ac2 – 26. By contrast, corticosterone provoked an increase in serum growth hormone (GH) which was ablated by central but not peripheral administration of anti‐annexin 1 pAb. IL‐1β (i.c.v. or i.p.) did not affect basal GH but, when given centrally but not peripherally, it abolished the corticosterone‐induced hypersecretion of GH. Annexin 1Ac2 – 26 (i.c.v.) also produced an increase in serum GH which was prevented by central injection of IL‐1β. The results support the hypothesis that the acute regulatory actions of glucocorticoids on hypothalamo‐pituitary‐adrenocortical function require annexin 1. They also provide novel evidence that the positive influence of the steroids on GH secretion evident within this timeframe is effected centrally via an annexin 1‐dependent mechanism which is antagonized by IL‐1β. British Journal of Pharmacology (2001) 134, 887–895; doi:10.1038/sj.bjp.0704324

Aberrant inflammation and resistance to glucocorticoids in Annexin 1−/−Mouse

“…In models of acute inflammation in the rodent, such as the zymosan-inflamed air pouch, our chief findings were that the administration of Anx-1neutralizing antibodies exacerbated inflammation as assessed by PMN influx, cytokine and eicosanoid synthesis, and resolution of the response (53). In models designed to mimic activation of the HPA axis during infection or inflammation, passive immunization blocked the inhibitory effects of exogenous corticosterone or dexamethasone on IL-1β-induced increases in adrenocorticotrophic hormone (54,55). Similarly, passive immunization studies have suggested that the capacity of glucocorticoids to counter the regulatory action of cytokines on the secretion of growth hormone and prolactin is dependent on Anx-1 (55).…”

Annexin 1: a paracrine/juxtacrine mediator of glucorticoid action in the neuroendocrine system

“…The subcellular distribution of annexin 1 within these tissues is regulated by GCs. [8][9][10][11] Thus, in addition to inducing de novo annexin 1 synthesis, the steroids promote the translocation of annexin 1 from within the cell (intracellular pool) to the outer cell surface (pericellular pool) where it is retained by a Ca 2þ -dependent mechanism. The data from binding studies 15 and from the functional studies described above suggest that this process of externalization provides an important mechanism by which annexin 1 gains access to binding sites (putative receptors) on the outer surface of endocrine cells and thereby exerts paracrine/juxtacrine regulatory actions on peptide release.…”

“…In vivo, the inhibitory effects of exogenous GCs (corticosterone or dexamethasone) on the release of ACTH driven by IL-1 (given centrally or peripherally) and other cytokines are readily quenched by central or peripheral administration of anti-annexin 1 antisera. 7,8 Furthermore, annexin 1 and peptides derived from its N-terminal mimic the inhibitory actions of the steroids. Similarly, the capacity of the steroids to suppress the evoked release of ACTH and CRH/AVP in vitro from pituitary and hypothalamic tissue respectively over a 2-3-h period is mimicked by annexin 1 and abolished by drugs which interfere with the activity (neutralizing antisera) or synthesis (e.g.…”

Annexin 1-Dependent Actions of Glucocorticoids in the Anterior Pituitary Gland: Roles of the N-Terminal Domain and Protein Kinase C

“…It is also strongly expressed in the neuroendocrine system (2,3), particularly 1) in the anterior pituitary gland, where it is abundant in the S100-positive folliculostellate cells (4) and also expressed in endocrine cells (5), and 2) in specific loci in the hypothalamus, notably the median eminence and the paraventricular, arcuate and periventricular nuclei (2). Further evidence of a role for ANXA1 in the regulation of ACTH and PRL secretion has been derived in vitro from studies using antisense probes directed against ANXA1 mRNA (10,11) and in vivo by the use of immunoneutralization strategies (10,12,13) and ANXA1 peptides (6,13). Binding and functional studies suggest that this process of externalization provides an important mechanism whereby ANXA1 gains access to binding sites (putative receptors) on the outer surface of cells and thereby exerts paracrine/autocrine regulatory actions on peptide release.…”