Abstract
The secretory insulin-like growth factor-binding protein-3 (IGFBP-3) induces apoptosis via both insulin-like growth factor-I (IGF-I)-dependent and -independent mechanisms. Here, we have examined the effects of IGFBP-3 on Leydig cell apoptosis, proliferation and steroidogenesis. Immunohistochemical analysis of testes of rats at different ages revealed that IGFBP-3 is expressed first after 20 days of postnatal life and is present at a high level in the adult testis. In addition, Western blotting showed that the expression of IGFBP-3 in Leydig cells isolated from 60-day-old rats is higher than in 40-day-old animals. The rate of DNA synthesis (as assessed by incorporation of 3H-thymidine in vitro) in Leydig cells from 40-day-old rats is reduced by IGFBP-3, which also blocks the promotion of cell survival by IGF-I. Moreover, IGFBP-3 induces apoptosis in Leydig cells and, at the same time, attenuates the anti-apoptotic action of IGF-I. Furthermore, IGF-I stimulates secretion of IGFBP-3, -4, and -2 by Leydig cells. The pro-inflammatory cytokine tumor necrosis factor- α induces apoptosis in these same cells and increases their secretion of IGFBP-3 and IGFBP-4. These findings provide the first evidence that IGFBP-3 acts as a pro-apoptotic effector of Leydig cells and can also block the positive effect of IGF-I on cell survival. In addition, IGFBPs appear to modulate interactions between IGF-I and pro-inflammatory cytokines in the testis, suggesting possible participation of these proteins in processes such as testicular inflammation and cancer.
Highlights
Insulin-like growth factors (IGFs) are involved in cell metabolism, growth, differentiation, and survival (1) in most organs, including those of the reproductive axis [1,2,3]
Since insulin-like growth factor-binding protein-3 (IGFBP-3) regulates insulin-like growth factor-I (IGF-I) bioavailability and IGF-I is involved in the processes of differentiation, steroidogenesis, and apoptosis in Leydig cells, we studied the modulation of IGFBPs on the effects of IGF-I at the time of IGF-I peak expression in the testis
On postnatal day 10 no expression of IGFBP-3 was found (Figure 1A), at 20 days of age, Leydig cells (LC) stained positively for IGFBP-3 (Figure 1C); at 60 days of age Leydig cells (LC) stained positively (Figures 1H-1J). These findings are in good agreement with the results of Western blotting (Figure 2), which revealed that expression of IGFBP-3 by cultures of Leydig cells isolated from 60-day-old rat testis was 3.2 -fold higher than in the case of 20-day-old testis and 2.3-fold higher than that of testis of 40-day-old rats (Figure 2)
Summary
Insulin-like growth factors (IGFs) are involved in cell metabolism, growth, differentiation, and survival (1) in most organs, including those of the reproductive axis [1,2,3]. The activities of these factors are regulated by a family of six high affinity-binding proteins (IGFBP-1–6), which determine IGF bioavailability in circulating fluids and the cellular environment [1,4,5]. IGFBP-2 and -3 are the most abundant IGFBPs in this organ [9] and large amounts of IGFBP-3 are produced by Sertoli and Leydig cells [9,11]. Both FSH and (Bu)2cAMP markedly lower IGFBP-3 levels in Sertoli cells [11] and this binding protein can either inhibit or enhance the effects on Leydig cells steroidogenesis depending on the surrounding conditions [9,12]
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