title: Cytokine-mediated regulation of ovarian function: interleukin-1 inhibits gonadotropin-induced androgen biosynthesis.
abstract: Resident ovarian macrophages have long been recognized as potential in situ regulators of ovarian function, presumably through local paracrine secretion of regulatory molecules (i.e. cytokines). One such macrophage product, interleukin-1 (IL-1) has recently been shown to exert profound regulatory effects at the level of the ovarian granulosa cell. In this report, we examine the possibility that the adjacent theca-interstitial (androgen-producing) cell may also be a site of IL-1 reception and action. The basal accumulation of androsterone, the major androgenic steroid synthesized by whole ovarian dispersates from immature rats, in the presence of insulin (1 microgram/ml), increased 8- to 9-fold after treatment with human CG (1 ng/ml). Although IL-1 alpha or IL-1 beta (10 ng/ml) by themselves were without effect on basal androsterone accumulation, both cytokines (IL-1 beta greater than IL-1 alpha) inhibited human CG hormonal action (in the presence of insulin) in a dose-dependent manner, the maximal inhibitory effect being 75%. Similar results were obtained when using highly purified theca-interstitial cells derived from the same animal model suggesting that IL-1-attenuated androgen biosynthesis is due, at least in part, to IL-1 acting directly at the level of the theca-interstitial cells. The IL-1 effect proved relatively specific since all other known interleukins (IL-1, IL-3, IL-4, IL-5, and IL-6) were without effect. Moreover, IL-1 beta action was effectively immunoneutralized when concurrently applied with anti-IL-1 beta (but not nonimmune) sera. Significantly, the antigonadotropic action of IL-1 could not be accounted for by a decrease in the viable cell mass. Tracer studies with radiolabeled steroid substrates suggested that IL-1-attenuated ovarian androsterone accumulation is due, if only in part, to inhibition of transformations catalyzed by (theca-interstitial) 17 alpha-hydroxylase/17:20 lyase, stimulation of theca-interstitial (or granulosa 20 alpha-hydroxysteroid dehydrogenase-mediated conversions, or both. Taken together, these findings indicate that relatively low concentrations of IL-1, possibly originating from somatic ovarian cells or resident ovarian macrophages, are capable of exerting an inhibitory effect upon gonadotropin-supported androgen production. As such, these and previous observations suggest that intraovarian IL-1 may play a dual regulatory role in the developing ovarian follicle by targeting both the granulosa and theca-interstitial cells as its sites of action.
authors.affiliation: Department of Obstetrics/Gynecology, University of Maryland, School of Medicine, Baltimore 21201.
authors.forename: A
authors.initials: A
authors.lastname: Hurwitz
authors.forename: D W
authors.initials: DW
authors.lastname: Payne
authors.forename: J N
authors.initials: JN
authors.lastname: Packman
authors.forename: C L
authors.initials: CL
authors.lastname: Andreani
authors.forename: C E
authors.initials: CE
authors.lastname: Resnick
authors.forename: E R
authors.initials: ER
authors.lastname: Hernandez
authors.forename: E Y
authors.initials: EY
authors.lastname: Adashi
mesh_terms: D000738:Androsterone / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008954:Models, Biological; D010053:Ovary / Q000187:drug effects / Q000502:physiology*; D011284:Pregnenolone / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D013256:Steroids / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; D007375:Interleukin-1; D011994:Recombinant Proteins; D013256:Steroids; D011284:Pregnenolone; D000738:Androsterone