Sy. Chun et al., INTERLEUKIN-1-BETA SUPPRESSES APOPTOSIS IN RAT OVARIAN FOLLICLES BY INCREASING NITRIC-OXIDE PRODUCTION, Endocrinology, 136(7), 1995, pp. 3120-3127
A growing body of evidence suggests that intraovarian interleukin-1 be
ta (IL-1 beta) may play an intermediary role in the ovulatory process.
Furthermore, induction of nitric oxide (NO) by IL-1 beta has been rep
orted in a wide variety of tissues. As the majority of ovarian follicl
es undergo an atretic degeneration process involving apoptotic cell de
ath, we set out to determine whether IL-1 beta rescues follicles from
apoptosis and the possible involvement of NO. Preovulatory follicles o
btained from PMSG-primed rats were cultured for 24 h in serum-free med
ium with or without hormone treatments. After culture, follicular apop
totic DNA fragmentation was analyzed by autoradiography of size-fracti
onated DNA labeled at 3'-ends with [P-32]dideoxy-ATP. Follicular NO pr
oduction was also determined by a colorimetric method. Treatment with
IL-1 beta dose-dependently suppressed the spontaneous onset of apoptos
is in cultured follicles, but stimulated NO production. In contrast, t
he addition of IL-1 receptor antagonist eliminated both effects of IL-
1 beta, confirming receptor mediation. Follicles treated with sodium n
itroprusside, a NO generator, or an analog of cGMP, the second messeng
er for NO, also showed decreased follicle apoptosis. Moreover, the add
ition of N-G-monomethyl-L-arginine, a NO synthase inhibitor, reversed
both IL-1 beta stimulation of NO production and suppression of apoptos
is, suggesting a mediatory role of NO in these IL-1 beta effects. Gona
dotropins also prevent follicle apoptosis. Of interest, treatment with
hCG stimulated NO production, and the hCG suppression of follicle apo
ptosis and stimulation of NO production were partially blocked by cotr
eatment with IL-1 receptor antagonist; indicating the mediation of end
ogenous IL-1 beta. Treatment with IL-1 beta also stimulated a small in
crease in the production of cAMP, estrogen, and progesterone. Taken to
gether, these findings suggest that IL-1 beta is a survival factor for
ovarian follicles, and its action is partially mediated via NO and cG
MP generation, Moreover, part of the suppressive action of gonadotropi
ns on follicle apoptosis is mediated by endogenously produced IL-1 bet
a.