title: Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is strongly induced by ACTH in adrenocortical cells.
abstract: 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 +/- 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 3'-5' adenosine monophosphate, but was not observed in response to angiotensin II, IGF-1, fibroblast growth factor-2, transforming growth factor-beta1, 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.
authors.affiliation: INSERM Unit 244, Department of Molecular and Structural Biology, Commissariat ê l'Energie Atomique, Grenoble, France.
authors.forename: N
authors.initials: N
authors.lastname: Quirin
authors.forename: M
authors.initials: M
authors.lastname: Keramidas
authors.forename: J
authors.initials: J
authors.lastname: Garin
authors.forename: E
authors.initials: E
authors.lastname: Chambaz
authors.forename: J J
authors.initials: JJ
authors.lastname: Feige
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; D000324:Adrenocorticotropic Hormone