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PubMed1991

The role of calcium in follicle-stimulating hormone signal transduction in Sertoli cells.

Sertoli cells are hormonally regulated by follicle-stimulating hormone (FSH) acting upon a G-protein-linked cell surface FSH receptor. FSH increases intracellular cyclic AMP but the involvement of other signal transduction mechanisms including intracellular calcium in FSH action are not proven. Using freshly isolated rat Sertoli cells we measured cytosolic free ionized calcium levels by dual-wavelength fluorescence spectrophotometry using the calcium-sensitive fluorescent dye Fura2-AM. The cytosolic calcium concentration in unstimulated Sertoli cells was 89 +/- 2 nM (n = 151 experiments) and was markedly increased by either calcium channel ionophores (ionomycin, Bay K8644) or plasma membrane depolarization consistent with the presence of voltage-sensitive and -independent calcium channel in Sertoli cell membranes. Ovine FSH stimulated a specific, sensitive (ED50, 5.0 ng of S-16/ml), and dose-dependent (maximal at 20 ng/ml) rise in cytosolic calcium commencing within 60 s to reach levels of 192 +/- 31 nM after 180 s and lasting for at least 10 min. The effect of FSH was replicated by forskolin, cholera toxin, and dibutyryl cyclic AMP, suggesting that cyclic AMP may mediate the FSH-induced rise in cytosolic calcium. The FSH-induced rise in cytosolic calcium required extracellular calcium and was abolished by calcium channel blockers specific for dihydropyridine (verapamil, nicardipine), nonvoltage-gated (ruthenium red) or all calcium channels (cobalt). Thus FSH action on Sertoli cells involves a specific, rapid, and sustained increase in cytosolic calcium which requires extracellular calcium and involves both dihydropyridine-sensitive, voltage-gated calcium channels and voltage-independent, receptor-gated calcium channels in the plasma membranes of rat Sertoli cells. The replication by cyclic AMP of the effects of FSH suggests that calcium may be a signal-amplification or -modulating mechanism rather than an alternate primary signal transduction system for FSH in Sertoli cells.

Animals↗

PubMed2003

Rat testicular germ cells and Sertoli cells release different types of bioactive transforming growth factor beta in vitro.

Several in vivo studies have reported the presence of immunoreactive transforming growth factor-beta's (TGF-beta's) in testicular cells at defined stages of their differentiation. The most pronounced changes in TGF-beta1 and TGF-beta2 immunoreactivity occurred during spermatogenesis. In the present study we have investigated whether germ cells and Sertoli cells are able to secrete bioactive TGF-beta's in vitro, using the CCl64 mink lung epithelial cell line as bioassay for the measurement of TGF-beta. In cellular lysates, TGF-beta bioactivity was only observed following heat-treatment, indicating that within these cells TGF-beta is present in a latent form. To our surprise, active TGF-beta could be detected in the culture supernatant of germ cells and Sertoli cells without prior heat-treatment. This suggests that these cells not only produce and release TGF-beta in a latent form, but that they also release a factor which can convert latent TGF-beta into its active form. Following heat-activation of these culture supernatant's, total TGF-beta bioactivity increased 6- to 9-fold. Spermatocytes are the cell type that releases most bioactive TGF-beta during a 24 h culture period, although round and elongated spermatids and Sertoli cells also secrete significant amounts of TGF-beta. The biological activity of TGF-beta could be inhibited by neutralizing antibodies against TGF-beta1 (spermatocytes and round spermatids) and TGF-beta2 (round and elongating spermatids). TGF-beta activity in the Sertoli cell culture supernatant was inhibited slightly by either the TGF-beta1 and TGF-beta2 neutralizing antibody. These in vitro data suggest that germ cells and Sertoli cells release latent TGF-beta's. Following secretion, the TGF-beta's are converted to a biological active form that can interact with specific TGF-beta receptors. These results strengthen the hypothesis that TGF-beta's may play a physiological role in germ cell proliferation/differentiation and Sertoli cell function.

Animals↗

PubMed1985

Identification of a spectrin-like protein in Sertoli cells.

Sertoli cells prepared from rats ages 15 and 25 days were shown to contain a spectrin-like protein. Indirect immunofluorescence with monospecific antimouse erythrocyte immunoglobulin G (IgG) and with monospecific antimouse brain spectrin IgG revealed specific staining in Sertoli cells. Both antibodies precipitated two spectrin-like peptides of 240,000 and 235,000 daltons from cells solubilized with octyl glucoside. Proteins from Sertoli cell membranes were separated by electrophoresis on polyacrylamide gels containing sodium dodecyl sulfate and electrophoretically transferred to nitrocellulose membrane. Incubation of nitrocellulose membrane with either of the two antibodies, followed by horseradish peroxidase conjugated to second antibody, revealed only the larger, or alpha, spectrin subunit (Western blots). Both antibodies were used to provide immunoautoradiographic identification of the spectrin-like protein. In this procedure, spectrin and Sertoli cell membranes were shown to compete with [125I]-labeled spectrin from mouse erythrocytes for binding to antimouse erythrocyte spectrin IgG. Finally, two-dimensional proteolytic mapping of the 240,000- and 235,000-dalton peptides demonstrated limited spot homology with rat erythrocyte spectrin. However, subcellular fractions from Sertoli cells all contained a spectrin-like protein showing high homology from fraction to fraction. It is concluded that Sertoli cells contain a spectrin-like protein that is seen in cell fractions prepared by centrifugation, i.e., mitochondria, microsomes, nuclei, cytoplasm, and plasma membranes. Although homology with spectrin from erythrocytes or brain is not seen in peptide maps, the alpha subunit shares antigenic determinants with spectrin from erythrocytes. The beta subunit is believed to be precipitated by antispectrin as the result of binding to the alpha subunit, since the beta subunit shows no detectable antigenic homology with that of spectrin.

Animals↗

PubMed1999

Role of class B scavenger receptor type I in phagocytosis of apoptotic rat spermatogenic cells by Sertoli cells.

Rat Sertoli cells phagocytose apoptotic spermatogenic cells, which consist mostly of spermatocytes, in primary culture by recognizing phosphatidylserine (PS) exposed on the surface of degenerating spermatogenic cells. We compared the mode of phagocytosis using spermatogenic cells at different stages of spermatogenesis. Spermatogenic cells were separated into several groups based on their ploidy, with purities of 60-90%. When the fractionated spermatogenic cell populations were subjected to a phagocytosis assay, cells with ploidies of 1n, 2n, and 4n were almost equally phagocytosed by Sertoli cells. All the cell populations exposed PS on the cell surface, and phagocytosis of all cell populations was similarly inhibited by the addition of PS-containing liposomes. Class B scavenger receptor type I (SR-BI), a candidate for the PS receptor, was detected in Sertoli cells. Overexpression of the rat SR-BI cDNA increased the PS-mediated phagocytic activity of Sertoli cell-derived cell lines. Moreover, phagocytosis of spermatogenic cells by Sertoli cells was inhibited in the presence of an anti-SR-BI antibody. Finally, the addition of high density lipoprotein, a ligand specific for SR-BI, decreased both phagocytosis of spermatogenic cells and incorporation of PS-containing liposomes by Sertoli cells. In conclusion, SR-BI functions at least partly as a PS receptor, enabling Sertoli cells to recognize and phagocytose apoptotic spermatogenic cells at all stages of differentiation.

Animals↗

PubMed2001

Role of the transcriptional coactivator CBP/p300 in linking basic helix-loop-helix and CREB responses for follicle-stimulating hormone-mediated activation of the transferrin promoter in Sertoli cells.

Sertoli cells are the epithelial cells responsible for the onset of pubertal development and the maintenance of spermatogenesis in the adult. Transferrin is one of the major secretory products expressed by differentiated Sertoli cells. Investigation of the transcriptional control of transferrin gene expression provides insight regarding the regulation of Sertoli cell differentiation. The optimal activation of the mouse transferrin promoter (mTf) by FSH requires the synergistic actions of the cAMP response element-binding protein (CREB) binding to the cAMP response element-like proximal region II (PRII) and the basic helix-loop-helix (bHLH) binding to the E-box. Proximal region II alone is sufficient for cAMP-mediated activation. The proximity of the PRII and E-box (220 base pairs apart) suggests the possibility of interaction between CREB and bHLH proteins. Such an interaction can be mediated by transcriptional integrators such as CREB-binding protein (CBP) and/or p300 and may stabilize the binding of trans-acting factors to their respective cis-elements. Such an interaction may also provide a mechanism for cell-specific promoter activation. The hypothesis tested in this study was that CBP/p300 is required for the synergistic activation of the transferrin promoter involving PRII and E-box through the formation of a ternary complex. In the Sertoli cells, both CBP and p300 proteins are expressed. The effect of CBP/p300 on transferrin promoter activation and, hence, Sertoli cell function was studied by using antisense oligonucleotides (AS-oligo). In the presence of CBP/p300 AS-oligo, activity of the FSH-induced mTf-chloramphenicol acetyl transferase (CAT) was significantly lower as compared to the respective controls. Interestingly, AS-oligo had no effect on cAMP-induced activation of the transferrin promoter reporter construct (mTf-CAT). Mutations in the E-box (EB*) significantly reduced the FSH response. The presence of AS-oligo had no further effect on the FSH-mediated activation of the EB*-mTf-CAT construct but reduced cAMP-mediated activation. Mutations in the CRE-like PRII (PRII*) also significantly reduced the FSH response. Activation of the PRII*-mTf-CAT in response to cAMP was completely abolished. The presence of AS-oligo had no further effect on the FSH- or cAMP-mediated activation of the PRII*-mTf-CAT construct. In Sertoli cells, CBP/p300 was coimmunoprecipitated with CREB and the bHLH protein E47. These observations suggest that CBP/p300 appears to be involved in regulating FSH-mediated activation of the transferrin promoter by linking bHLH and CREB activities.

Animals↗

PubMed1998

Plasminogen activator inhibitor-1 is expressed in cultured rat Sertoli cells.

Sertoli cells secrete plasminogen activators (PAs) on both sides of the blood-testis barrier, i.e., in the basal and apical compartments of the seminiferous tubules, whereas peritubular cells secrete plasminogen activator inhibitor-1 (PAI-1), a fast-acting and specific PA inhibitor. While it is likely that PAI-1 produced by peritubular cells counteracts the basal secretion of PA, the nature of the PA inhibitor acting in the apical compartment remains to be demonstrated. In the present study, we showed that Sertoli cells recovered from 20-day-old rats and cultured contained a transcript of 3-3.2 kilobases, which hybridized specifically to a PAI-1 cDNA probe (Northern blot). We verified that the observed PAI-1 transcript could not result solely from the peritubular cells (weakly contaminating the Sertoli cell cultures), by comparing PAI-1 mRNA levels of Sertoli and peritubular cells recovered from 20-day-old rats and cultured. We also demonstrated that cultured Sertoli cells secreted a protein that complexed with tissue-type PA (zymography), indicating that it was biologically active. This protein comigrated with purified PAI-1 as a doublet of 46 and 49 kDa (Western blot). The trophic hormone FSH decreased PAI-1 messenger RNA as well as immunoreactive PAI-1 protein (probably via the cAMP protein kinase A pathway), whereas transforming growth factor ss1 and basic fibroblast growth factor (in a nanomolar concentration) increased both of these. These observations support the hypothesis that PAI-1 is expressed by Sertoli cells and is under a complex hormonal (FSH) and paracrine and/or autocrine control exerted at least by basic fibroblast growth factor and transforming growth factor ss1.

Alkaline Phosphatase↗

PubMed1983

Large-cell calcifying sertoli cell tumor of the testis. An ultrastructural, immunocytochemical, and biochemical study.

This report describes the ultrastructural and hormonal characteristics of the recently described large-cell calcifying Sertoli cell tumor of the testis, a rare subtype of pure Sertoli cell tumor. The ultrastructural findings showed similarity to normal Sertoli cells, pure Sertoli cell tumors, Sertoli cells in azoospermic human testes, and the Sertoli cell component of Sertoli-Leydig cell tumors. Ultrastructure indicated features common to steroid-producing cells. Testosterone and estradiol were demonstrated in the tumor by immunocytochemical and biochemical methods.

Basement Membrane↗

PubMed2004

The role of calcium in signal transduction processes in Sertoli cells.

Sertoli cells play a pivotal role in regulation and maintenance of spermatogenesis. They are hormonally regulated predominantly by follicle-stimulating hormone (FSH) and testosterone (T). Although FSH and T have distinct mechanisms of action they act synergistically in promoting spermatogenesis. Stimulation of freshly isolated Sertoli cells with FSH evokes a prompt rise in cytosolic calcium which is quantitatively reproduced by cAMP. The cytosolic calcium response to FSH in Sertoli cells is predominantly attributable to serial signaling after the generation of endogenous cAMP. Calcium homeostasis of Sertoli cells may also be regulated by cAMP-independent metabolism. Vasoactive testicular paracrine hormones such as angiotensin II (AII) and vasopressin acting via inositol triphosphate generation induce cytosolic calcium rise predominantly derived from the thapsigargin-sensitive endoplasmic reticulum. Investigations involving androgens action on cytosolic calcium reveal a common mechanism of action between the peptide and steroid regulators of Sertoli cell function, indicating that cytosolic calcium ions may represent a unifying biochemical mechanism that could explain the synergism of FSH and T. Androgens rapidly and specifically increase cytosolic calcium, consistent with a plasma membrane site of action. This argues for the possible existence of a short term non-genomic signaling pathway in hormonal regulation of Sertoli cell function in addition to the classical longer term, slower genomic response.

Acid-Base Equilibrium↗

PubMed2006

Pharmacological profile of inhibition of the chloride channels activated by extracellular acid in cultured rat Sertoli cells.

Sertoli cells from mammalian testis are key cells involved in the development and maintenance of stem cell spermatogonia as well as in the secretion of a Cl(-) and K(+)-rich fluid into the lumen of seminiferous tubules. The pharmacology and contribution of Cl(-) channels to the physiology of Sertoli cells were investigated using whole-cell patch clamp and iodide efflux experiments applied to cultured rat Sertoli cells. We characterized an outwardly rectifying Cl(-) current stimulated by various acid species including the physiologically relevant lactic acid. Using the iodide efflux technique, the pharmacological properties of this Cl(-) current, noted ICl(acid), revealed Ca(2+)-independent inhibition by DIDS (IC(50) = 27 microM), glibenclamide (IC(50) = 31 microM) and DPC (IC(50) = 86 microM). ICl(acid) was neither affected by calix[4]arene nor by 9-AC. The order of potency for inhibition of ICl(acid) is DIDS approximately glibenclamide > DPC >> calix[4]arene, 9-AC. For comparison, the inhibitory profile of the swelling- and ATP-activated Cl(-) currents in Sertoli cells is DPC = DIDS >> glibenclamide = 9-AC for ICl(swell) and DPC = 9-AC = DIDS >> glibenclamide for ICl(ATP). This description provides new insights into the physiology and pharmacology of the endogenous Cl(-) channels expressed and potentially involved in fluid secretion in Sertoli cells.

Adenosine Triphosphate↗

PubMed2005

Metabolism of amino acids by cultured rat Sertoli cells.

Sertoli cells support spermatogenesis both spatially and energetically; for this reason, these cells have important adaptations. The energetic metabolism of Sertoli cells was adapted to provide lactate and pyruvate to developing germ cells, because these substrates are essential for spermatocytes and spermatids. In this study, we investigated whether Sertoli cells use alanine, leucine, valine, and glycine as energetic substrates and whether the simultaneous addition of other nutrients, such as glucose and glutamine, might affect the metabolism of these amino acids. Alanine, leucine, valine, and glutamine are almost totally oxidized to CO2 by these cells. In contrast, glycine has been demonstrated to be a poor energetic substrate, being mainly incorporated into proteins, and their metabolism did not change in the presence of palmitic acid, glucose, and/or glutamine. The metabolism of the 3 other amino acids was modified by palmitic acid; besides, glucose changed alanine, leucine, and valine oxidation. Glutamine decreased the oxidation of alanine, leucine, and valine to CO2. Conversely, both alanine and leucine decreased the oxidation of glutamine. Our present findings show that Sertoli cells can adapt its energy metabolism to the oxidative substrates available to fulfill their role in spermatogenic energetic supply.

Alanine↗

PubMedDate not supplied

Identification and characterization of a beta-adrenergic receptor in hamster Sertoli cells.

Sertoli cells cultured from immature hamsters contain a beta-adrenergic receptor which is coupled to the cAMP second messenger system. Thus, isoproterenol, epinephrine, and norepinephrine, which act via beta-adrenergic receptors, all stimulate cAMP accumulation in Sertoli cells cultured for 4-5 days. This cAMP response to isoproterenol is inhibited stereospecifically by the beta-receptor blocker, propranolol. It is also sensitive to inhibition by beta-adrenergic antagonists in this order of potency: nonspecific beta receptor antagonists, propranolol, timolol, hydroxypindolol greater than beta 1 selective antagonists, oxyprenolol, metoprolol much much greater than beta 2 selective antagonist, butoxamine. Butoxamine was at least 1000-fold less sensitive than either the nonspecific or the beta 1 selective antagonists at inhibiting the response of either isoproterenol (nonspecific), dobutamine (beta 1 selective) or zinterol (beta 2 selective). The hamster Sertoli cell beta receptor is, therefore, predominantly of the B1 subtype. This beta receptor mediated increase in cAMP is sensitive to homologous desensitization and is stimulated synergistically by forskolin. In addition, Seroli cells freshly isolated from immature hamsters contain an active beta receptor. However, this beta receptor mediated increase in cAMP is dependent on the type of trypsin used in the cell preparation. In agreement with Kierszenbaum et al (1985), freshly isolated Sertoli cells from immature rats never responded to the catecholamines regardless of the type of trypsin used; indicating an important physiologic difference between rat and hamster Sertoli cells.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Tonic inhibition of adenylate cyclase in cultured hamster Sertoli cells.

Sertoli cells cultured from immature hamsters respond to FSH with a dose-related increase in cAMP accumulation. Pertussis toxin acts synergistically with FSH to stimulate cAMP accumulation. This effect of pertussis toxin indicates that Sertoli cell adenylate cyclase is under tonic inhibition due to the activity of the Ni inhibitory transducer. The acetylcholine receptor antagonists atropine or tubocurarine, or the opioid antagonist naltrexone, have no effect on the FSH-induced stimulation of cAMP accumulation, suggesting that neither acetylcholine nor opioids are responsible for the inhibition of Sertoli cell cyclase. While exogenous adenosine is inhibitory, adenosine deaminase augments the ability of FSH to stimulate cAMP accumulation, but not to the level of pertussis toxin. This indicates that the Sertoli cells produce endogenous adenosine that is at least partially responsible for the tonic inhibition of adenylate cyclase. Other possibilities for the tonic inhibition of cyclase include other Sertoli cell products, germ cell products, peritubular cell products or an action of FSH itself through both stimulatory and inhibitory transducers.

Adenosine↗

PubMed1999

Toxic effects of octylphenol on cultured rat spermatogenic cells and Sertoli cells.

Alkylphenols, including the estrogenic 4-tert-octylphenol (OP), are environmental pollutants. Because administration of OP to adult male rats impairs spermatogenesis and OP has been shown to be toxic to aquatic animals and to mammalian splenocytes in vitro, we studied whether OP exerts direct toxic effects on cultured spermatogenic cells and Sertoli cells isolated from male rats. Cell viability was assessed with a Live/Dead Eukolight viability/cytotoxicity kit. Culture of mixed spermatogenic cells from adult rats with 10(-8) M OP or Sertoli cells from 19- to 21-day-old rats with 10(-12) M OP, but not with 0.08% EtOH (vehicle) or 10(-6) M 17beta-estradiol (E2) or dexamethasone (DEX), significantly decreased the percentage of viable cells after 24 h of treatment. None of the treatments significantly altered total cell number. Flow cytometric analyses of spermatogenic cells revealed that exposure to 10(-4) or 10(-6) M OP yielded abnormal relative ploidy classes. Four hours of treatment with 10(-6) M OP, but not with 10(-6) M E2 or DEX, caused significant chromatin condensation in Sertoli cells as observed with acridine orange staining. The decreased percentage of viable cells after 24 h of exposure to 10(-6) M OP remained when Sertoli cells were cultured in Ca2+-free medium. Sertoli cells contained nuclei of reduced size and labeled 3'-OH DNA ends as detected by microscopic analyses when the cells had been incubated for 24 h with 10(-6) M OP but not with vehicle or 10(-6) M E2 or DEX. The results demonstrate that OP, but not E2 or DEX, is directly toxic to cultured rat spermatogenic cells and Sertoli cells and suggest that this toxic effect in Sertoli cells is exerted through Ca2+-independent apoptosis.

Acridine Orange↗

PubMed1981

Differential effects of luteinizing hormone-releasing hormone on follicle-stimulating hormone-dependent responses in rat granulosa cells and Sertoli cells in vitro.

The abilities of LHRH and a potent LHRH agonist ([D-Ser-(But),6, des-Gly-NH210]LHRH ethylamide) inhibit FSH responses by rat granulosa cells and Sertoli cells in vitro have been compared. Granulosa cells isolated from 22- or 25-day-old diethylstilbestrol-primed rats and cultured under defined conditions for 48 h with NIH-FSH-S13 (300 ng/ml) or cholera toxin (0.1 microgram/ml) showed increased aromatase activity, as determined by the release of 3H2O from [1 beta-3H]testosterone. LHRH (10(-7) M) or th agonist (10(-8) M) added simultaneously with FSH or cholera toxin inhibited the effects on the release of 3H2O without influencing the protein content of the cell cultures. A smaller stimulation of 3H2O production occurred with (Bu)2cAMP (1.0 mM) plus 3-isobutyl-l-methylxanthine (0.1 mM), and this was partially suppressed in the presence of LHRH or the agonist. Parallel studies with Sertoli cells from 15- or 20-day-old rats demonstrated that culture under appropriate conditions with FSH, cholera toxin, or (Bu)2cAMP (0.5 mM) for 24 h caused an increase in cellular aromatase activity and enhanced secretion into the medium of plasminogen activator. However, no inhibition by LHRH (10(-7) or 10(-9) M) or the agonist (10(-6) or 10(-8) M) occurred when the peptides were added either simultaneously or 24 h before the stimulatory agent. Similarly, Sertoli cells from 11-day-old rats treated daily with LHRH agonist for 5 days in culture, showed no inhibition of aromatase activity after a 4-h stimulation with FSH or (Bu)2cAMP. FSH dose-response curves (0-300 ng/ml) for aromatase activity were shown to be similar after 5 days of culture with or without 10(-8) M LHRH agonist, indicating that the LHRH did not cause a shift in the sensitivity to FSH. The lack of inhibition was seen in Sertoli cell cultures maintained at 37 or 32 C. The enzyme digestion method used to isolated Sertoli cells was not responsible for the lack of effects of LHRH, since cell cultures prepared without the aid of proteolytic enzymes showed similar FSH stimulation of aromatase activity in the presence or absence of 10(-8) M agonist. Further, there was no evidence of degradation of the LHRH agonist when incubated with Sertoli cell cultures. From these studies, we conclude that 1) granulosa cells and Sertoli cells from immature rats differ in their responses to LHRH, and 2) the immature Sertoli cell is an unlikely target for a direct inhibiting influence of LHRH on spermatogenesis.

Animals↗

PubMed1995

Interactions between germ cells and Sertoli cells in the testis.

The "nurse cell" function of Sertoli cells in spermatogenesis was originally tacitly assumed on the basis of the anatomical relationships between cells in the testis. In mammals, from very early in prenatal development to the onset of meiosis and to the ultimate production of spermatozoa, the relationship between the germinal cells and the Sertoli cells is important and apparently obligatory. The experimental evidence supports the notion that the primary endocrine regulation of spermatogenesis via FSH and testosterone is manifested through actions on the Sertoli cells. Although diverse strategies are used by Sertoli cells to support germ cell development, one of the most important roles of Sertoli cells is the regulation of the intratubular and intercellular environment adluminal to the tight junctional complexes. The meiotic and post-meiotic germ cells are sequestered by Sertoli-Sertoli junctional complexes in an adluminal compartment that is isolated from the serum or lymph. As a result of this sequestering activity, the secretion products of the Sertoli cells and the meiotic germ cells determine the composition of this local environment that can influence meiosis as well as spermatid and spermatocyte development. Evidence is accumulating that paracrine and autocrine factors from Sertoli and germ cells are important in the functioning of both cell types. While it is important to know what Sertoli cells and germ cells make, it is equally important to know when they make it. Distinct but well-defined groups of germ cells interact with Sertoli cells in a cyclic pattern. These recurring groups of germ cells define the cycle of the seminiferous epithelium during which sperm are produced in an asynchronous fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Identification of a novel human granzyme B inhibitor secreted by cultured sertoli cells.

Sertoli cells have long since been recognized for their ability to suppress the immune system and protect themselves as well as other cell types from harmful immune reaction. However, the exact mechanism or product produced by Sertoli cells that affords this immunoprotection has never been fully elucidated. We examined the effect of mouse Sertoli cell-conditioned medium on human granzyme B-mediated killing and found that there was an inhibitory effect. We subsequently found that a factor secreted by Sertoli cells inhibited killing through the inhibition of granzyme B enzymatic activity. SDS-PAGE analysis revealed that this factor formed an SDS-insoluble complex with granzyme B. Immunoprecipitation and mass spectroscopic analysis of the complex identified a proteinase inhibitor, serpina3n, as a novel inhibitor of human granzyme B. We cloned serpina3n cDNA, expressed it in Jurkat cells, and confirmed its inhibitory action on granzyme B activity. Our studies have led to the discovery of a new inhibitor of granzyme B and have uncovered a new mechanism used by Sertoli cells for immunoprotection.

Acute-Phase Proteins↗

PubMed1994

Immunolocalization of albumin and transferrin in germ cells and Sertoli cells during rat gonadal morphogenesis and postnatal development of the testis.

The localization of albumin and transferrin was examined immunohistochemically in germ cells and Sertoli cells during rat gonadal morphogenesis and postnatal development of the testis. These proteins appeared as early as the 13th day of gestation in migrating primordial germ cells before Sertoli cell differentiation. In the fetal testis, strong immunoreactivity was only detected in the gonocytes. In the prepubertal testis, spermatogonia, primary spermatocytes, and some Sertoli cells accumulate albumin and transferrin. At puberty, different patterns of immunostaining of the germ cells were observed at the various stages of the cycle of the seminiferous epithelium. Diplotene spermatocytes at stage XIII, spermatocytes in division at stage XIV, and round spermatids at stages IV-VIII showed maximal staining. Labeling was evident in the cytoplasm of adult Sertoli cells. Albumin and transferrin staining patterns paralleled each other during ontogenesis.

Animals↗

PubMed2002

Utility of immunostaining for S-100 protein subunits in gonadal sex cord-stromal tumors, with emphasis on the large-cell calcifying Sertoli cell tumor of the testis.

This study concerns the immunohistochemical localization of S-100 alpha, S-100 beta, and whole brain S-100 (wbS-100) in testicular large-cell calcifying Sertoli cell tumor (LCCSCT). We examined 8 LCCSCTs (7 benign and 1 malignant), 6 Sertoli cell tumors not otherwise specified (SCTs-NOS), 6 Leydig cell tumors (LCTs), 5 ovarian Sertoli-Leydig cell tumors (SLCTs), and 7 gonadoblastomas (GBLs). The 8 LCCSCTs showed immunoreactivity for S-100 alpha, S-100 beta, and wbS-100. Five of the 6 LCTs and the Leydig cell components in the ovarian SLCTs stained positively for S-100 alpha and wbS-100 but were negative for S-100 beta. SCTs-NOS and the Sertoli cell components in the SLCTs occasionally showed focal and weak/moderate positivity for S-100 alpha, S-100 beta, and wbS-100. Sex cord cells of the GBLs were positive for S-100 beta and wbS-100 and negative for S-100 alpha. Germ cell elements of the GBLs were negative for S-100 alpha, S-100 beta, and wbS-100. In nonneoplastic testicular parenchyma adjacent to the above-mentioned tumors, there was S-100 alpha reactivity in Leydig cells, rete testis, and a few Sertoli cells. S-100 beta reactivity was seen in a few Sertoli cells, Schwann cells, and some endothelial cells. WbS-100 reactivity was present in Leydig cells, a few Sertoli cells, rete testis, Schwann cells, and some endothelial cells. The results indicate that S-100 alpha and S-100 beta can potentially be used as immunohistochemical markers for LCCSCT, especially when differentiating it from LCT, which may mimic LCCSCT on routine histopathology. Although the biological significance of both S-100 subunits expression in LCCSCT remains unknown, these notable calcium-binding proteins may be associated with the characteristic calcification in LCCSCT through regulation of calcium levels in the tumor cells.

Biomarkers↗