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Activin-A Inhibits Proopiomelanocortin Messenger RNA Accumulation and Adrenocorticotropin Secretion of AtT20 Cells

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute La Jolla, California 92037

Address requests for reprints to: Louise M. Bilezikjian, Ph.D., The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037.

Abstract

The complexity of corticotropic cell regulation by multiple central and peripheral factors is well recognized. The present study provides evidence for the participation of an additional factor in the regulation of this cell type of the anterior pituitary. Using the clonal AtT20 cell line as a model for corticotropes, homodimeric activin-A was observed to suppress basal ACTH secretion and POMC mRNA accumulation by approximately 50%. These effects required prolonged treatment with activin-A and were concentration dependent; the half-maximum concentration was in the range of 30–50 pM. Consistently, AtT20 cells were found to express specific high affinity binding sites for [¹²⁵I]activin-A. The simultaneous addition of inhibin-A along with increasing concentrations of activin-A did not alter the characteristics of the inhibition of ACTH secretion by activin-A alone. This is in contrast to observations with gonadotropes of the anterior pituitary as well as a number of other cell types in which inhibin-A can partially antagonize the biological actions of activin-A. The results may suggest the participation of a subclass of activin receptors that mediate effects on ACTH secretion and POMC mRNA accumulation. As previously shown, the incubation of AtT20 cells with a synthetic glucocorticoid, dexamethasone, attenuated basal ACTH secretion and POMC expression in a concentration-dependent manner. The inhibition of both of these parameters by activin-A, however, was independent of glucocorticoids, because the two agents were additive in their actions. In addition to effects on secretion and mRNA levels, treatment with activin-A also inhibited the rate of proliferation of AtT20 cells. In view of the recent evidence for the presence of activin-B, and possibly activin-A, within the anterior pituitary, the results of this study suggest that locally secreted activins may exert a tonic inhibitory influence on corticotropes.

FOOTNOTES

This work was supported in part by NIH Grants DK-26741 – 11 and HD-13527–12. Research was conducted in part by the Clayton Foundation for Research, California Division.

^* Clayton Foundation Senior Investigator.

Received for publication June 5, 1991. Revision received July 18, 1991. Accepted for publication July 18, 1991.

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