Interleukin-1beta regulates pituitary follistatin and inhibin/activin betaB mRNA levels and attenuates FSH secretion in response to activin-A.
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 betaB and activin-B (betaBbetaB) 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-1beta (IL-1beta) is one of several cytokines known to also influence the reproductive axis. IL-1beta inhibits the hypothalamo-pituitary-gonadal (HPG) axis by suppressing GnRH and gonadal steroid production. Because several pituitary cell types, including follistatin-producing folliculo-stellate cells, are targets of IL-1beta, cytokine effects on gonadotrope function were evaluated using cultured rat anterior pituitary cells. Activin-A (0.01 to 1 nM; 24h) increased basal FSH secretion approximately 2-fold. IL-1beta (0.005 to 0.5 nM) by itself had no effect on basal FSH secretion. However, IL-1beta attenuated FSH secretion in response to all concentrations of activin-A. These results suggest 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-1beta (0.005 to 5 nM) stimulated follistatin and inhibin/activin betaB mRNA accumulation in a time-dependent manner. These in vitro effects of IL-1beta were blocked by the specific IL-1 receptor antagonist (IL-lra) and were not mimicked by either rhIL-6 or lipopolysaccharide (LPS). Treatment of intact male rats with LPS (50 microg, i.v.), which increases plasma IL-1beta and induces IL-1beta 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-1beta can modulate gonadotrope responses to activins by influencing the local balance of activin-B and follistatin within the pituitary.
Bilezikjian
L M
LM
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA 92037, USA.
Turnbull
A V
AV
Corrigan
A Z
AZ
Blount
A L
AL
Rivier
C L
CL
Vale
W W
WW
D028341:Activins; D000818:Animals; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D038681:Follistatin; D006023:Glycoproteins / Q000235:genetics*; D007265:Inhibins / Q000235:genetics* / Q000494:pharmacology*; D007375:Interleukin-1 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides; D010455:Peptides / Q000235:genetics*; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D038681:Follistatin; D006023:Glycoproteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010455:Peptides; D012333:RNA, Messenger; C044147:activin B; D028341:Activins; C048617:myelopeptides; D007265:Inhibins; D005640:Follicle Stimulating Hormone