Regulation of tissue inhibitor of metalloproteinases-1 in rat Sertoli cells: induction by germ cell residual bodies, interleukin-1alpha, 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 vitro. This study was performed to elucidate further the cellular origin of testicular 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 increased by the injection of FSH-S17 to hypophysectomized rats. Primary cultures of both peritubular and Sertoli cells showed basal expression of TIMP-1 mRNA. In contrast, we were unable to detect TIMP-1 mRNA in Leydig cells, freshly isolated immature germ cells (primary spermatocytes and spermatids), or residual bodies. We further show that treatment of Sertoli cells with 8-(4-chlorophenyl)thio-cAMP (8-CPTcAMP) in combination with 12-O-tetradecanoylphorbol 13-acetate (TPA) or Ca(2+) inducers (calcium ionophore A23187 or thapsigargin) had additive (TPA) and synergistic effects (Ca(2+)) 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 cells were strongly increased by residual bodies, as well as by the cytokine interleukin-1alpha. TIMP-1 was not up-regulated by either 8-CPTcAMP or interleukin-1alpha 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 Sertoli cells, suggesting a role of nuclear TIMP-1 in these cells. In conclusion, our data show that secretion of TIMP-1 from Sertoli cells is highly regulated by hormonal and local processes in the testis, indicating that TIMP-1 is of physiological importance during both testicular development and spermatogenesis.
Grønning
L M
LM
Institute of Medical Biochemistry, University of Oslo, N-0317 Oslo, Norway. l.m.gronning@basalmed.uio.no
Wang
J E
JE
Ree
A H
AH
Haugen
T B
TB
Taskén
K
K
Taskén
K A
KA
D000818:Animals; D015152:Blotting, Northern; D020013:Calcium Signaling / Q000502:physiology; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D005854:Germ Cells / Q000502:physiology*; D007016:Hypophysectomy; D015151:Immunoblotting; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D019899:Paracrine Communication / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000502:physiology*; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism*; D013347:Subcellular Fractions / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
D007375:Interleukin-1; D019715:Tissue Inhibitor of Metalloproteinase-1; D012313:RNA; D005640:Follicle Stimulating Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C