Regulation of tissue inhibitor of metalloproteinases-1 in rat sertoli cells: Induction by germ fell residual bodies, interleukin-1 alpha, and second messengers

In the testis, FSH has been shown to induce the expression and secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) from Sertoli cells in vi tro. This study was performed to elucidate further the cellular origin of t esticular TIMP-1 and its expression by hormonal and paracrine factors. This is the first report on the expression of testicular TIMP-1 in vivo. TIMP-1 mRNA in whole testis was decreased after hypophysectomy and strongly incre ased by the injection of FSH-S17 to hypophysectomized rats. Primary culture s of both peritubular and Sertoli cells showed basal expression of TIMP-1 m RNA, In contrast, we were unable to detect TIMP-1 mRNA in Leydig cells, fre shly isolated immature germ cells (primary spermatocytes and spermatids), o r residual bodies. We further show that treatment of Sertoli cells with 8-( 4-chlorophenyl)thio-cAMP (8-CPTcAMP) in combination with 12-O-tetradecanoyl phorbol 13-acetate (TPA) or Ca2+ inducers (calcium ionophore A23187 or thap sigargin) had additive (TPA) and synergistic effects (Ca2+) on the level of TIMP-1 mRNA and secreted protein. We also show that both the level of TIMP -1 mRNA and secreted protein from Sertoli tells were strongly increased by residual bodies, as well as by the cytokine interleukin-1 alpha. TIMP-1 was not up-regulated by either 8-CPTcAMP or interleukin-1 alpha in peritubular cells. In contrast to the regulated secretory fraction of TIMP-1, we also detected constitutively expressed immunoreactive TIMP-1 in the nucleus of S ertoli cells, suggesting a role of nuclear TIMP-1 in these cells. In conclu sion, our data show that secretion of TIMP-1 from Sertoli cells is highly r egulated by hormonal and local processes in the testis, indicating that TIM P-1 is of physiological importance during both testicular development and s permatogenesis.