Mediator Of Glucocorticoid Action Research Articles

Regulation of proliferation, apoptosis and cell cycle in gastrointestinal disorders

Carcinogenesis is a multifactorial process representing the accumulation of acquired and genetic defects, and it has become apparent that many gastrointestinal cancers originate from a state of chronic inflammation. Advances in the field of inflammation-induced carcinogenesis over the past several years have focused on the creation of agonists or antagonists of cytokines and pathways regulating proliferation and apoptosis, and include advances such as the discovery of pharmacological inhibitors of the histone deacetylase (HDAC) family of transcriptional co-repressors, which induce apoptosis of neoplastic cells; discovery of natural products, such as curcumin, which have been shown to regulate cytokine expression; and further investigation into the role of annexin A1, a downstream mediator of glucocorticoid action, in the regulation of inflammation, to name a few.

MAPK phosphatases as novel targets for rheumatoid arthritis

Background: Rheumatoid arthritis (RA) represents a challenge for therapeutic interventions due to complex inflammatory signalling pathways underlying its pathogenesis. The MAPK signalling network, a major effector limb of the inflammatory lesion, is an attractive therapeutic target. MAPK phosphatases (MKPs), endogenous negative regulators of MAPK signalling, have received increasing recognition as modulators of inflammatory and immune responses, and hence as a potential therapeutic avenue for RA. Objective: To present the rationale for therapeutically targeting MAPK signalling and explore the case for addressing MKP1 as a novel therapeutic strategy for RA. Methods: We summarise literature describing the importance of MAPK signalling in RA and review reports describing the roles of MKPs in modulating innate and adaptive immune responses. Finally we expand on the role of MKP1 in RA pathogenesis and explore data defining MKP1 as a mediator of glucocorticoid action. Conclusion: MKP1 constitutes an exciting, novel potential therapeutic target for RA.

The influence of 17β-estradiol on annexin 1 expression in the anterior pituitary of the female rat and in a folliculo-stellate cell line

Annexin 1 (ANXA1) is a Ca2+- and phospholipid-binding protein that plays an important role as a mediator of glucocorticoid action in the host-defence and neuroendocrine systems. Sex differences in hypothalamo–pituitary–adrenal (HPA) axis activity are well documented and a number of studies have demonstrated that gonadal steroids act as regulators of HPA activity. The aim of this study was to investigate the effect of ovariectomy and 17β-estradiol replacement, and estrous cycle stage, on anterior pituitary ANXA1 content. The amount of anterior pituitary ANXA1 determined by western blotting varied with estrous cycle stage with a peak at estrus declining to a trough at proestrus. Ovariectomy resulted in a significant (P<0·05) decrease in anterior pituitary ANXA1 content. Administration of 17β-estradiol (1 μg/100 g) significantly (P<0·01) increased anterior pituitary ANXA1 expression in the ovariectomized animals. In contrast, there was no change in pituitary ANXA1 content in response to 17β-estradiol in adrenalectomized and adrenalectomized/ovariectomized rats. Treatment of TtT/GF cells, a folliculo-stellate cell line, with 17β-estradiol (1·8–180 nM) increased ANXA1 mRNA expression and increased the amount of ANXA1 protein externalized in response to a dexamethasone stimulus. These results indicate that 17β-estradiol stimulates ANXA1 expression in the anterior pituitary and in vivo an adrenal factor contributes to the mechanism of action.

Expression, subcellular localization and phosphorylation status of annexins 1 and 5 in human pituitary adenomas and a growth hormone‐secreting carcinoma

Annexin 1 (ANXA1), a 37-kDa protein, plays an important role as a mediator of glucocorticoid action in the anterior pituitary gland and has been implicated in the processes of tumorigenesis in a number of other tissues. As a prelude to examining the potential role of ANXA1 in the pathophysiology of pituitary tumours, this study examined the expression, phosphorylation status and distribution of ANXA1 and the closely related protein, annexin 5 (ANXA5), in a series of pituitary adenomas and in two carcinomas. Forty-two human pituitary adenomas were examined. Parallel studies were performed on normal pituitary tissue, obtained postmortem, a GH-secreting carcinoma and a grade 4 astrocytoma. The tissue was processed for analysis of ANXA1 mRNA and protein expression by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis and immunogold electron-microscopic histochemistry. Parallel measures of ANXA5 mRNA and protein were also made. ANXA1 mRNA and protein were detected in all but three adenomas studied; the protein was localized mainly, but not exclusively, to nonendocrine cells. ANXA5 expression was more variable and was contained within both endocrine and nonendocrine cells of these tumours. In comparison with the adenomas, the GH-secreting carcinoma showed abundant expression of both ANXA1 and ANXA5, with intense ANXA1 staining in some but not all tumour/endocrine cells. A serine-phosphorylated species of ANXA1 was detected in all pituitary tumours studied; by contrast, tyrosine-phosphorylated ANXA1 was detected in only four adenomas and in the GH carcinoma. ANXA1 and ANXA5 were also expressed in abundance in the astrocytoma. The results demonstrate expression of both ANXA1 and ANXA5 in human pituitary tumours and thus raise the possibility that these proteins influence the growth and/or functional activity of the tumours.

Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse.

The 37-kDa protein annexin 1 (Anx-1; lipocortin 1) has been implicated in the regulation of phagocytosis, cell signaling, and proliferation and is postulated to be a mediator of glucocorticoid action in inflammation and in the control of anterior pituitary hormone release. Here, we report that mice lacking the Anx-1 gene exhibit a complex phenotype that includes an altered expression of other annexins as well as of COX-2 and cPLA2. In carrageenin- or zymosan-induced inflammation, Anx-1-/- mice exhibit an exaggerated response to the stimuli characterized by an increase in leukocyte emigration and IL-1beta generation and a partial or complete resistance to the antiinflammatory effects of glucocorticoids. Anx-1-/- polymorphonuclear leucocytes exhibited increased spontaneous migratory behavior in vivo whereas in vitro, leukocytes from Anx-1-/- mice had reduced cell surface CD 11b (MAC-1) but enhanced CD62L (L-selectin) expression and Anx-1-/- macrophages exhibited anomalies in phagocytosis. There are also gender differences in activated leukocyte behavior in the Anx-1-/- mice that are not seen in the wild-type animals, suggesting an interaction between sex hormones and inflammation in Anx-1-/- animals.

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

1. Our previous studies have identified 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 effecting 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 effectively 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 specific anti-annexin 1 monoclonal antibody quenched the corticosterone-induced suppression of secretagogue-evoked GH release while an isotype matched control antibody was without effect. 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 unaffected 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 effected at a point distal to the formation of cyclic AMP and Ca(2+) entry.

Hormonal Regulation of the mRNA for Cysteine-Rich Intestinal Protein in Rat Jejunum During Maturation

Cysteine-rich intestinal protein (CRIP) has been implicated as an important zinc-binding protein in the rat intestine. However, its specific role remains undefined. As an approach to the ultimate elucidation of the function of CRIP, we have explored the role of glucocorticoids and L-thyroxine (T4) in the increase of CRIP mRNA that occurs during postnatal development. Hydrocortisone administration on day 10 elicited a precocious increase of CRIP mRNA. The response to hydrocortisone was readily detectable 12 h after injection. Lack of endogenous glucocorticoids in rat pups adrenalectomized on day 9 impeded but did not prevent the normal rise of CRIP mRNA. Furthermore, injections of dexamethasone (DEX) on days 10, 16, and 18 led to a loss of responsiveness of CRIP mRNA as the pups matured. The administration of T4 alone resulted in a small increase of CRIP mRNA, whereas when combined, T4 and DEX synergistically raised the concentration of CRIP mRNA. All of these patterns of response to hormone manipulation indicate the possibility that CRIP is a mediator of glucocorticoid action on the developing intestine. They do not appear to support the hypothesis that CRIP plays a role in zinc transport during the postnatal period. The potent effects of glucocorticoids and T4 on CRIP mRNA levels should provide useful tools for further investigations in this area.

Hormonal Regulation of the mRNA for Cysteine‐Rich Intestinal Protein in Rat Jejunum During Maturation

SummaryCysteine‐rich intestinal protein (CRIP) has been implicated as an important zinc‐binding protein in the rat intestine. However, its specific role remains undefined. As an approach to the ultimate elucidation of the function of CRIP, we have explored the role of glucocorticoids and L‐thyroxine (T4) in the increase of CRIP mRNA that occurs during postnatal development. Hydrocortisone administration on day 10 elicited a precocious increase of CRIP mRNA. The response to hydrocortisone was readily detectable 12 h after injection. Lack of endogenous glucocorticoids in rat pups adrenalectomized on day 9 impeded but did not prevent the normal rise of CRIP mRNA. Furthermore, injections of dexamethasone (DEX) on days 10, 16, and 18 led to a loss of responsiveness of CRIP mRNA as the pups matured. The administration of T4 alone resulted in a small increase of CRIP mRNA, whereas when combined, T4 and DEX synergistically raised the concentration of CRIP mRNA. All of these patterns of response to hormone manipulation indicate the possibility that CRIP is a mediator of glucocorticoid action on the developing intestine. They do not appear to support the hypothesis that CRIP plays a role in zinc transport during the postnatal period. The potent effects of glucocorticoids and T4 on CRIP mRNA levels should provide useful tools for further investigations in this area.