Transcriptional and posttranscriptional regulation of intraovarian insulin-like growth factor-binding proteins by interleukin-1 beta (IL-1 beta): Evidence for IL-1 beta as an antiatretic principal

Intraovarian interleukin-1 (IL-1), a putative intermediary in the ovulatory cascade, has recently been implicated as an antiatretic agent. Given the r eported antigonadotropic and thus atretogenic potential of granulosa cell-d erived insulin-like growth factor-binding proteins (IGFBPs), we evaluated t he ability of IL-1 beta to regulate ovarian IGFBP-4 and -5, the IGFBP speci es elaborated by the rat granulosa cell. Treatment of whole ovarian dispers ates of immature rat origin with increasing concentrations of IL-1 beta for 96 h resulted in substantial and significant time-dependent inhibition of IGFBP-4 and IGFBP-5 transcripts compared with that in untreated controls. T he IL-1 effect proved relatively specific in that no significant alteration s in IGFBP transcripts were observed in the presence of select ovarian agon ists, including transforming growth factor-alpha, tumor necrosis factor-alp ha, endothelin-1, hepatocyte grow th factor, keratinocyte growth factor, or basic fibroblast growth factor. The inhibitory effect of IL-1 beta on ovar ian IGFBP-4 and -5 expression was almost completely reversed in the presenc e of IL-1 receptor antagonist, suggesting mediation via a specific IL-1 rec eptor. The addition of actinomycin D to IL-1 beta-pretreated whole ovarian dispersates produced a pattern of (IGFBP-4 and -5) messenger RNA decay indi stinguishable from that noted for the untreated control group. Medium condi tioned by IL-1 beta-treated (but not untreated) whole ovarian dispersates d isplayed a marked diminution in the relative content of the IGFBP-4 and IGF BP-5 proteins (24- and 28- to 29-kDa proteins, respectively). Medium condit ioned by IL-lp-treated (but not untreated) whole ovarian dispersates proteo lyzed [I-125]IGFBP-5 (but not IGFBP-4) into fragments with apparent molecul ar masses of 18 and 14 kDa, respectively. In conclusion, our present observ ations demonstrate the ability of IL-1 to 1) inhibit the steady state level s of transcripts corresponding to IGFBP-4 and -5 in a time-dependent, relat ively specific, and receptor-mediated fashion; 2) suppress the accumulation of the corresponding IGFBP proteins; and 3) stimulate the activity of the IGFBP-5-directed (but not IGFBP-4) endopeptidase, a posttranscriptional phe nomenon. Our findings also suggest, by inference, that the IL-1 beta-mediat ed inhibition of IGFBP-4 and -5 transcripts is due in part to a decrease in the rate of transcription of the corresponding genes and not to a change i n the stability of the relevant messenger RNAs. Consequently, the ability o f IL-1 to influence ovarian IGFBP economy appears multifaceted, comprising both transcriptional and posttranscriptional effects. To the extent that IG FBP-4 and -5 constitute atretogenic agents, our present findings support th e view that IL-1 beta may play an antiatretic role in the context of ovaria n physiology.