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Interleukin-1ß Regulates Pituitary Follistatin and Inhibin/Activin ß_B mRNA Levels and Attenuates FSH Secretion in Response to Activin-A

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037; North Western Injury Research Centre, University of Manchester, Manchester M13 9PT, United Kingdom

Address all correspondence and requests for reprints to: Louise M. Bilezikjian, The Salk Institute, Clayton Foundation Labs for Peptide Biology, 10010 North Torrey Pines Road, La Jolla, California 92037.

Activins and follistatins regulate all levels of the reproductive axis, including the pituitary where they stimulate and inhibit FSH production, respectively. Gonadotropes are known to express inhibin/activin ß_B and activin-B (ß_Bß_B) functions as an autocrine modulator of FSH production. By contrast, the mRNA for the activin-binding protein, follistatin, is present in most pituitary cells and folliculo-stellate cells may be the major source of the protein secreted by the anterior pituitary. Interleukin-1ß (IL-1ß) is one of several cytokines known to also influence the reproductive axis. IL-1ß inhibits the hypothalamo-pituitary-gonadol (HPG) axis by suppressing GnRH and gonadal steroid production. Because several pituitary cell types, including follistatin-producing folliculo-stellate cells, are targets of IL-1ß, cytokine effects on gonadotrope function were evaluated using cultured rat anterior pituitary cells. Activin-A (0.01 to 1 nM; 24 h) increased basal FSH secretion ~2-fold. IL-1ß (0.005 to 0.5 mM) by itself had not effect on basal FSH secretion. However, IL-1ß attenuated FSH secretion in response to all concentrations of activin-A. These results suggests that the cytokine might stimulate the local production of a factor, such as follistatin, that antagonizes the action of activin-A. RNase protection analysis indicated that IL-1ß (0.005 to 5 nM) stimulated follistatin and inhibin/activin ß_B mRNA accumulation in a time-dependent manner. These in vitro effects of IL-1ß were blocked by the specific IL-1 receptor antagonist (IL-1ra) and were not mimicked by either rhIL-6 or lipopolysaccharide (LPS). Treatment of intact male rats with LPS (50 µg, iv), which increases plasma IL-1ß and induces IL-1ß expression in many tissues, including the pituitary, produced similar time-dependent increases in pituitary follistatin and inhibin/activin subunit mRNA levels. These results suggest that IL-1ß can modulate gonadotrope responses to activins by influencing the local balance of activin-B and follistatin within the pituitary.

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