Tumor necrosis factor-alpha attenuation of luteinizing hormone-stimulated androstenedione production by ovarian theca-interstitial cells: inhibition at loci within the adenosine 3',5'-monophosphate-dependent signaling pathway.

Abstract:

:Tumor necrosis factor-alpha (TNF) blocks LH-stimulated androstenedione production by immature rat theca-interstitial cells (TIC) in vitro. The mechanism for TNF inhibition of LH-induced androstenedione is unknown and was investigated. LH stimulation of androstenedione synthesis in TIC is mediated via a cAMP-dependent signaling pathway. LH-stimulated cAMP in TIC-conditioned medium was reduced in a biphasic manner by TNF at 1 and 48 h, but not at 4 and 24 h. To determine whether inhibition of cAMP resulted from TNF interference of LH binding, TIC were given TNF for 24 and 48 h, and LH binding was determined. TNF inhibited LH binding at 24 and 48 h. Scatchard analysis revealed a TNF-induced decrease in LH receptor number without altered affinity. TIC were given TNF and cAMP analogs [N6-benzoyl-cAMP, 8-thiomethyl-cAMP, 8-(6-aminohexyl)amino-cAMP, and N6-2'-O-(Bu)2cAMP], which selectively activate cAMP-dependent protein kinase (PKA) type I and/or PKA type II, respectively. At 48 and 96 h, TNF blocked androstenedione production stimulated by all combinations of cAMP analogs; however, androstenedione synthesis recovered by 48 h after removal of TNF. Peak PKA activity in TIC was observed at 30 min in the presence of LH or cAMP analogs. LH- or cAMP analog-directed PKA activity was inhibited after concomitant exposure to TNF; however, a 24-h pretreatment with TNF did not affect cAMP analog-stimulated PKA activity. The results indicate that in the modulation of steroidogenesis, TNF acts at multiple sites in the PKA pathway. First, TNF suppresses LH-stimulated cAMP production by TIC. Secondly, inhibition of cAMP may result from TNF attenuation of LH binding, and thirdly, TNF inhibits PKA activity of TIC and, thus, attenuates androstenedione production.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Zachow RJ,Tash JS,Terranova PF

doi

10.1210/endo.133.5.8404680

subject

Has Abstract

pub_date

1993-11-01 00:00:00

pages

2269-76

issue

5

eissn

0013-7227

issn

1945-7170

journal_volume

133

pub_type

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