Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is strongly induced by ACTH in adrenocortical cells

✍ Scribed by Nicolas Quirin; Michelle Keramidas; Jérôme Garin; Edmond Chambaz; Jean-Jacques Feige

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 214 KB
• Volume: 180
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/(sici)1097-4652(199909)180:3<372::aid-jcp8>3.0.co;2-g

✦ Synopsis

Besides its acute and chronic effects on corticosteroid synthesis, the pituitary adrenocorticotropic hormone (ACTH) regulates diverse adrenocortical biological functions including the synthesis of a number of mitochondrial, cytoplasmic, and secreted proteins. ACTH-induced secreted proteins are candidates to act as local extracellular relays of the hormone in either an autocrine or a paracrine manner.

In the present study, we report that stimulation of primary cultures of bovine adrenocortical (BAC) fasciculata cells with 10 nM ACTH for 24 h results in a mean 8 Ϯ 4-fold induction of the synthesis of a secreted protein presenting an apparent Mr of 21 kDa. Peptide microsequencing and Western blotting allowed us to identify this 21-kDa ACTH-induced protein as the tissue inhibitor of metalloproteinase-2 (TIMP-2). The induction of TIMP-2 by ACTH required transcription, was mimicked by 8-bromo cyclic 3Ј-5Ј adenosine monophosphate, but was not observed in response to angiotensin II, IGF-1, fibroblast growth factor-2, transforming growth factor-␤1, or cortisol treatments. ACTH stimulated TIMP-2 mRNA levels by a factor 4, whereas TIMP-1 mRNA levels were not affected and TIMP-3 mRNA remained undetectable. The biological activity of TIMP-2 varied accordingly, as we observed that the conditioned medium of ACTH-treated BAC cells was four times more potent at inhibiting gelatinolytic activity than was the conditioned medium of control cells. Because the proteolytic activity of both progelatinase-B and progelatinase-A secreted by BAC cells remained latent, whether in the presence or in the absence of ACTH, a paracrine rather than autocrine role is proposed for TIMP-2 in the adrenal cortex.