Evidence for the Role of Adenosine 5′-Triphosphate-Binding Cassette (ABC)-A1 in the Externalization of Annexin 1 from Pituitary Folliculostellate Cells and ABCA1-Transfected Cell Models

Abstract

Annexin 1 (ANXA1), a 37-kDa protein, is a member of the superfamily of Ca(2+)- and phospholipid-binding annexin proteins. In the anterior pituitary, ANXA1 is expressed mainly by folliculostellate (FS) cells and mediates the early delayed feedback inhibition exerted by glucocorticoids on the release of ACTH and other pituitary hormones. It has been previously demonstrated that TtT/GF cells (a FS cell line) express and externalize ANXA1 in response to glucocorticoid treatment. However, ANXA1 lacks a cleavable signal sequence and externalization is not affected by inhibitors of the secretory pathway. We have previously shown that glyburide, an ATP-binding cassette (ABC) transporter inhibitor, inhibits the externalization of ANXA1 from TtT/GF cells and pituitary tissue. Here we investigated whether ABCA1 is involved in ANXA1 externalization. The use of the ABCA1-transporter inhibitors geranyl-geranyl pyrophosphate and sulfobromophthalein significantly inhibited ANXA1 externalization. Partial silencing of ABCA1 expression in TtT/GF cells by siRNA also significantly decreased the amount of cell surface ANXA1. However, anterior pituitary tissue from ABCA1-null mice was found to externalize ANXA1 normally. Because compensation by other ABC family members may occur in vivo, ANXA1 externalization was studied in two transfection models: Xenopus oocytes injected with ABCA1 mRNA and AtT20 D1 corticoctroph cells cotransfected with ABCA1-green fluorescent protein and ANXA1. ABCA1-expressing oocytes, but not water-injected controls, were found to externalize ANXA1. Expression of ABCA1 in AtT20 D1 cells significantly increased the amount of cell surface ANXA1, compared with mock-transfected and ANXA1-only transfected controls. Together these data provide evidence for a role of ABCA1 in ANXA1 export.

The Anti-Inflammatory Role of Annexin-1 in Arthritis

“…Alternative pathways related to the secretion of Anx-1 have been recently proposed by CastroCaldas [56], Chapman, and Omer et al [57,58]. Exogenously applied Anx-1 or its N-terminal peptides result in potent anti-inflammatory effects in experimental animal models [10,21,59,60], which is consistent with the observation of Anx-1externalization in inflammatory human diseases and the hypothesis that extracellular or cell-surface Anx-1 is the key compartment where anti-inflammatory biological activity is exerted.…”

Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment

“…Nevertheless, AnxA1 can be detected in the plasma under conditions of inflammation or in the supernatant of activated endothelial cells 29,31 and hence alternative pathways for the secretion of AnxA1 have been proposed. One of these pathways includes the externalization via ABCA1 32 and endothelial expression of this transporter is protective in a mouse model of atherosclerosis. 33 However, additional studies are needed to understand the endogenous source of AnxA1 during hypercholesterolemia.…”

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

“…ANXA1 is expressed strongly in the S100-positive folliculo-stellate cells (FS cells) in the anterior pituitary (Traverso et al 1999) and in vivo almost total loss of FS cell ANXA1 immunoreactivity occurs in adrenalectomized rats which is replenished upon glucocorticoid replacement (Ozawa et al 2002). Functional and binding studies suggest that the glucocorticoid-induced translocation of ANXA1 via the ATP-binding cassette transporter ABCA1 (Chapman et al 2003, Omer et al 2006) is an important mechanism which enables the protein to access binding sites on the surface of the endocrine cells and thereby exert paracrine regulation on the release of ACTH and other pituitary hormones via surface binding proteins (Christian et al 1997). …”