Intraovarian tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible-14 ligand-receptor system limits ovarian preovulatory follicles from excessive luteinization.
In addition to gonadotropins, many ovarian paracrine factors are crucial for optimal follicle rupture, oocyte maturation, and luteinization. Based on DNA microarray analyses, we found that transcripts for the fibroblast growth factor-inducible-14 (Fn14) receptor are increased after LH/human chorionic gonadotropin (hCG) treatment of gonadotropin-primed immature mice or rats. Fn14 is the cognate receptor for TNF-related weak inducer of apoptosis (TWEAK), a TNF superfamily member. TWEAK transcripts also were detected in the ovary; however, their levels were not regulated by gonadotropins. In situ hybridization analyses indicated that the Fn14 receptor is expressed in the granulosa and cumulus cells of preovulatory follicles and, to a lesser extent, in theca cells. In contrast, in situ hybridization analyses revealed that TWEAK is primarily expressed in theca cells. In cultured granulosa cells pretreated with hCG to induce Fn14 receptor expression, treatment with TWEAK suppressed progesterone synthesis without accompanying changes in cAMP production. Furthermore, intrabursal injection of TWEAK suppressed ovarian progesterone content in gonadotropin-primed rats. In contrast, preovulatory follicles cultured in the presence of the Fn14 decoy, a recombinant protein containing the ligand-binding domain of Fn14, led to increases in progesterone production, presumably by antagonizing the actions of endogenous TWEAK. Likewise, ip injection of the Fn14 decoy enhanced serum progesterone levels with accompanying increases in transcript levels for several key steroidogenic enzymes. The present findings demonstrate a suppressive role of the TWEAK/Fn14 signaling system in the ovary. Following gonadotropin induction of ovulation, Fn14 is induced and could protect preovulatory follicles from excessive luteinization.
De
Ananya
A
Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA.
Park
Jae-Il
JI
Kawamura
Kazuhiro
K
Chen
Ruby
R
Klein
Cynthia
C
Rauch
Rami
R
Mulders
Sabine M
SM
Sollewijn Gelpke
Maarten D
MD
Hsueh
Aaron J W
AJ
D000818:Animals; D015153:Blotting, Western; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000074049:Cytokine TWEAK; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D017403:In Situ Hybridization; D034461:Luteinization / Q000378:metabolism*; D046228:Microarray Analysis; D006080:Ovarian Follicle / Q000378:metabolism* / Q000502:physiology; D010053:Ovary / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074050:TWEAK Receptor; D013799:Theca Cells / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D000074049:Cytokine TWEAK; D017931:DNA Primers; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C000613300:Tnfrsf12a protein, rat; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D011374:Progesterone