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PubMed1991

Radioimmunoassay for activin A/EDF. Method and measurement of immunoreactive activin A/EDF levels in various biological materials.

A radioimmunoassay (RIA) for the measurement of activin A, which is identical to erythroid differentiation factor (EDF), has been developed. A specific antiserum against activin A/EDF was raised in rabbits using a mixture of recombinant EDF and polyvinyl pyrrolidone. Of the compounds tested this polyclonal antibody cross-reacted only with bovine inhibin (3.2%) and human TGF-beta (4.2%). The least detectable value in this assay was 0.06 ng/tube. The within- and between-assay coefficients of variation at three different concentrations were 3.6-9.8% and 3.4-7.7%, respectively. Using this RIA, immunoreactive activin A/EDF levels in various biological fluids and tissues were examined. The dose-response curves of porcine follicular fluid and ovarian extract were parallel to the standard curve, and porcine follicular fluid contained high activin A/EDF immunoreactivity (1050 ng/ml). On gel chromatography of porcine follicular fluid, the major immunoreactivity was eluted in the same position as authentic activin A/EDF. Human placental extract and amniotic fluid had relatively high immunoreactive activin A/EDF levels (174 ng/g wet wt. and 63.9 ng/ml, respectively), but the dose-response curve of amniotic fluid was not parallel to the standard curve. Among rat tissues, the ovary showed the highest activin A/EDF immunoreactivity (163 ng/g wet wt.) much lower than that of porcine ovary (1020 ng/g wet wt.). Low immunoreactive activin A/EDF levels were detected in most parts of rat brain (8.7-14.2 ng/g wet wt.), except for the pituitary gland (70.0 ng/g wet wt.). The initial plasma half clearance time (t1/2) of exogenous activin A/EDF was 14 min in the rat and the plasma FSH concentration did not change significantly during this period. These results suggest that this RIA system has sufficient sensitivity and specificity to measure activin A/EDF concentrations in biological materials, and that the reproductive tissues are the main sources of activin A/EDF.

Activins↗

PubMed1992

Competitive protein binding assay for activin A/EDF using follistatin determination of activin levels in human plasma.

A sensitive and specific protein binding assay for activin A/EDF (activin) was developed using follistatin as a binding protein and [125I] labelled activin as a tracer. As 50% acetonitrile (CH3CN) separated free and follistatin-bound activin, plasma pretreated with an equal volume of CH3CN was used as the assay sample and B/F separation was also done with 50% CH3CN. The recovery of the assay was 85.0% and its sensitivity was 0.5 ng/ml. Crossreactivity with inhibin A was 1.8%. The mean plasma level of follistatin-free activin in normal subjects was 1.3 +/- 0.7%. (M +/- SD) ng/ml. Plasma free activin levels were generally elevated in patients with chronic renal failure or hematological diseases associated with anemia.

Activins↗

PubMed1990

[Effects of T-activin on the morphology of the thymus gland in experimental injury of the lower limbs in mice (anti-stress effect of T-activin)].

The effect of T-activin on thymic involution under the experimental trauma of femur was studied. T-activin in a dose of 1.0 micrograms/mouse was injected into young male (CBA X C57BL)F1 mice weighing 17.5-19.0 g before (I injection) or immediately after the fracture of the femur during 3 days. Morphometric analysis of the thymus was made 1, 5, 10 and 15 days after the trauma. It was found that T-activin suppressed the involution of the thymus, induced by the trauma, during the first 5 days and accelerate the process of its regeneration. It is suggested, that T-activin displays protective anti-stress effect on the mouse thymic involution.

Adjuvants, Immunologic↗

PubMed1992

A carboxyl-terminal truncated version of the activin receptor mediates activin signals in early Xenopus embryos.

The function of a carboxyl-terminal truncated version of the Xenopus activin receptor, encoded by a previously isolated gene XSTK2, was investigated in early embryos. The transcript corresponding to the truncated receptor gene was detected throughout embryonic development although the temporal expression pattern was different from that of an intact receptor. Injection of XSTK2 mRNA into early embryos resulted in the formation of a duplicated body axis. Mesoderm induction as evaluated by the activation of the alpha-actin gene in presumptive ectoderm (animal cap) treated with exogenous activin was significantly enhanced by the injection of XSTK2 mRNA. These results suggest that the truncated receptor is capable of transmitting the activin signal to the same extent as the native receptor.

Actins↗

PubMed1990

Activin-A modulates growth hormone secretion from cultures of rat anterior pituitary cells.

Activins, initially identified as FSH-releasing proteins, have now been shown to exert effects on other cell types of the anterior pituitary, including the somatotrophs. In the present study the inhibitory action of activin-A (beta A beta A) on GH secretion was characterized using primary cultures of rat anterior pituitary cells. Activin-A suppressed basal GH secretion for up to 72 h (the longest time tested). Immediately after the treatment period with activin-A, when the cells were thoroughly washed and further incubated with or without rat GH-releasing factor (rGRF), basal and stimulated GH secretion were partially inhibited as well. In parallel, activin-A pretreatment diminished rGRF-stimulated cAMP accumulation. The effects of activin-A were time- and concentration-dependent, with half-maximal inhibition occurring in the range of 20-30 pM activin-A. A minimum pretreatment time of 3 h was required for maximal effect, and when rGRF and activin-A were added simultaneously, no inhibition was evident. Secretory responses of activin-A-pretreated cells to rGRF were influenced by glucocorticoids. When cells were cultured in the presence of the synthetic glucocorticoid dexamethasone, pretreatment (72 h) with activin-A attenuated rGRF-stimulated GH secretion only during short (1-h), but not longer (3-h), exposure periods to the neuropeptide. In the absence of dexamethasone, rGRF-stimulated GH secretion was inhibited at all incubation times tested (up to 3 h). A 3-h exposure to the protein factor did not alter total (cellular plus secreted) immunoreactive GH levels, suggesting that the inhibition of secretion with the shorter treatment was not secondary to attenuated GH biosynthesis. However, longer (72-h) treatment with activin-A decreased total GH levels, indicating lower GH biosynthetic rates, as previously shown. Somatostatin is recognized as the primary negative modulator of GH secretion. Activin-A and SRIF inhibited GH secretion additively, suggesting distinct mechanisms of action for each. GH secretion in response to other secretagogues, such as 12-O-tetradecanoyl-phorbol-13-acetate, forskolin, cholera toxin, and 8-bromo-cAMP, was also suppressed after activin-A pretreatment. The presence of the RNA synthesis inhibitor actinomycin-D completely blocked the inhibitory effect of a 3-h activin-A pretreatment on subsequent rGRF-stimulated GH secretion. Pertussis toxin was only partially effective in preventing the inhibition by activin-A. The results of this study indicate that activin-A plays a crucial role as a modulator of somatotropic function, inhibiting GH secretion at the level of the secretory process and secondary to the inhibition of GH biosynthesis.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Isolation and characterization of native activin B.

To examine whether activin binds to follistatin, an activin-binding protein, to form a complex in vivo, we attempted to purify activin-follistatin complex from porcine follicular fluid. Our results thus obtained indicated that almost equimolar amounts of activins A, AB, and B are present as a complex with follistatin in the follicular fluid. Reverse-phase high performance liquid chromatography of the purified complex yielded follistatin and activins A, AB, and B. The activity of the purified activin B was found to be significantly lower than those of other activins in various assay systems such as stimulation of follicle-stimulating hormone secretion, induction of erythrodifferentiation, and potentiation of expression of gonadotropin receptors on ovarian cells. Moreover, binding of 125I-activin A to erythroleukemic cells which are activin-responsive was competed by activin B with approximately 10-fold lower potency compared with other activins. In contrast to these results, activin B was proved to have a potent Xenopus mesoderm-inducing activity, comparable with that of other activins. This indicates that, unlike activins A and AB, activin B can only elicit mesoderm-inducing activity and cannot function in other biological systems, suggesting a specific role of activin B in early development and unknown biological functions.

Activins↗

PubMed1991

Development-related effects of recombinant activin on steroid synthesis in rat granulosa cells.

Activin is structurally related to polypeptide growth factors such as transforming-growth factor-beta, which may have paracrine and/or autocrine functions in the ovaries. We have investigated the action of activin on granulosa cell steroidogenesis in vitro in relation to preovulatory follicular development in vivo. Estrogen-primed immature female rats received no other treatment (nondifferentiated granulosa cells), treatment with ovine (o) FSH (differentiated granulosa cells), or treatment with oFSH followed by human (h) CG (preovulatory granulosa cells) to stimulate preovulatory follicular development. Granulosa cells were isolated and cultured in the presence and absence of recombinant human activin-A using serum-free medium supplemented with 1.0 microM testosterone as an aromatase substrate and hFSH, hLH, forskolin, or 8-bromo-cAMP to stimulate steroid synthesis in vitro. After 48 h, medium was collected for measurement of estradiol (aromatase activity), progesterone, and cAMP. Basal steroid synthesis in nondifferentiated granulosa cells was unaffected by activin, but both aromatase activity and progesterone production induced by treatment with FSH in vitro were dosedependently enhanced up to 10-fold by the presence of activin. FSH-stimulated cAMP production was not measurably altered by activin; however, steroidogenesis induced by forskolin or 8-bromo-cAMP was significantly enhanced by the factor. Thus the effect of activin on steroidogenesis includes action at a subcellular level(s) distal to the production of cAMP. After gonadotropin treatment in vivo, granulosa cell aromatase activity and progesterone production showed divergent responses to activin in vitro. Basal-, FSH-, and LH-stimulated aromatase activity were all enhanced by activin in cultures of differentiated and preovulatory granulosa cells. However, whereas basal progesterone production was stimulated by activin in cultures of differentiated granulosa cells, in preovulatory granulosa cells it was inhibited. Moreover, in vitro stimulation of progesterone production by treatment of both differentiated and preovulatory granulosa cells with FSH or LH was suppressed by the presence of activin. Thus rat granulosa cells display development-related steroidogenic responses to activin, aromatase production becoming enhanced and progesterone production suppressed as follicular maturation progresses. These results further implicate activin as a local modulator of granulosa cell steroid synthesis in the ovaries, although its functional significance has yet to be established.

Activins↗

PubMed1992

Inhibition of progestin accumulation by activin-A in human granulosa cells.

The effects of activin and inhibin on steroidogenesis in the human ovary were investigated. Granulosa cells harvested from follicles of women undergoing oocyte recovery for in vitro fertilization were maintained in culture for 4 days before treatment in serum-free medium. Human recombinant inhibin-A and activin-A at concentrations of 100 ng/mL did not affect basal progesterone secretion (P greater than 0.05). Progesterone concentrations were increased 2- to 6-fold by hCG or FSH. Activin-A inhibited the progesterone response to hCG compared with that of cells treated with hCG alone (P less than 0.01). The effect of activin-A was dose dependent and significant at 16-18 h of treatment (P less than 0.01). Inhibin-A at the same concentrations as activin-A had no effect on the progesterone responses to hCG and FSH. The hCG-induced accumulation of 20 alpha-hydroxyprogesterone was also attenuated by simultaneous activin-A treatment compared to that in cells treated with hCG alone (P less than 0.01). To investigate the mechanism of action of activin-A, cells were treated with a cAMP analog (8-bromo-cAMP) or an activator of adenylate cyclase (forskolin), with or without activin-A. Activin-A had no effect on 8-bromo-cAMP-stimulated progesterone accumulation. Likewise, forskolin-stimulated progesterone accumulation was not affected by activin-A. The hCG-induced increase in intracellular cAMP was decreased by activin-A in the presence of a phosphodiesterase inhibitor, isobutylmethylxanthine (P less than 0.01). Thus, activin-A may inhibit progesterone production by suppression of gonadotropin-induced cAMP production. These results support an autocrine role of activin-A in the steroidogenic capacity of human ovarian cells.

Activins↗

PubMed1989

Regulation of Leydig cell function in primary culture by inhibin and activin.

Inhibin and activin are gonadal glycoproteins that selectively inhibit and stimulate FSH release, respectively. Previously we have reported that transforming growth factor-beta inhibited hCG-stimulated testosterone formation in mature Leydig cells. In the present study we evaluated the effects of other members of the transforming growth factor-beta family, inhibin and activin, on Leydig cell function. We found that activin (0.1-10 ng/ml) had no effect on basal testosterone formation, but inhibited hCG-stimulated testosterone formation in a dose-dependent manner. Activin (10 ng/ml) inhibited hCG-stimulated testosterone formation by 42%. Activin also inhibited hCG-stimulated cAMP formation. In the presence of activin (5 ng/ml), forskolin (10 microM)- and 8-bromo-cAMP (0.1 mM)-induced testosterone formation were reduced about one third. Conversions of pregnenolone and progesterone to testosterone were also blocked by activin. Interestingly, [125I]hCG binding to Leydig cells and forskolin-induced cAMP formation were not affected by the addition of activin. In contrast to activin, inhibin (0.1-10 ng/ml) had no effect on hCG-induced testosterone formation at any concentration used. However, the inhibitory effects of activin on Leydig cell function were reversed by the concomitant addition of inhibin. Our results suggest that activin inhibits testosterone formation by the Leydig cells derived from normal mature rats. Multiple steps of the steroidogenic pathway are affected by testosterone. Inhibin alone has no effect, but reverses the inhibitory action of activin.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1991

Activin-binding protein is present in pituitary.

A binding protein for activin was purified from bovine pituitary by affinity chromatography on dextran sulfate-Sepharose CL-4B and activin-Affi-Gel 10. A 52,700-fold purification over the starting crude homogenate was achieved. The purified preparation showed two bands of 36 and 33 kilodalton in sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. The ability of each form of the protein to specifically bind activin was determined by ligand blot analysis and binding competition study. Each protein was found to have the same NH2-terminus and its sequence was identical to that of follistatin, which is a specific inhibitor of identical to that of follistatin, which is a specific inhibitor of FSH release. Moreover, the binding protein was shown to inhibit the spontaneous FSH release from cultured pituitary cells as does follistatin. These properties are the same as activin-binding protein that we have obtained from rat ovary. These results support a conclusion that activin-binding protein/follistatin exists also in the pituitary. Activin-binding protein has an ability to inhibit the activin-induced augmentation of FSH release from cultured pituitary cells as does inhibin. However, the inhibitory pattern by the binding protein was quite distinct from that of inhibin, suggesting that there may be different mechanism(s) for their antagonistic actions. Stoichiometric inhibition as shown by gel filtration analysis indicates that activin-binding protein binds activin to form an inactive equimolar complex having neither stimulatory nor inhibitory activity for FSH secretion by the pituitary. These findings suggest that activin is actually involved in FSH secretion in the pituitary and that the activin action in the pituitary is regulated by activin-binding protein/follistatin.

Activins↗

PubMed1992

Activin-A stimulates the synthesis of gonadotropin-releasing hormone receptors.

The number of GnRH receptors on gonadotropes is regulated by GnRH as well as by heterologous modulators. We have used the density shift technique to measure the synthetic rate of GnRH receptors in pituitary cell cultures and found it to be stimulated by GnRH, an action that is antagonized by inhibin. In the present study, we evaluated the effects of activin-A on the GnRH receptor synthesis rate as well as effects of activin on stimulation of GnRH receptor synthesis by the homologous hormone. Recombinant human activin-A (50 ng/ml) was incubated with pituitary cell cultures from female weanling rats and the incorporation of densely labeled amino acids into receptors for GnRH was measured. The rate of GnRH receptor synthesis of cells treated with activin (50 ng/ml) together with either GnRH (0.1 ng/ml) or inhibin (12 ng/ml) was also quantified. Activin significantly stimulated the synthetic rate of GnRH receptors similarly to that observed after GnRH treatment (time for synthesis of half the population of GnRH receptors was 12.6 +/- 1.1, 16.1 +/- 1.3 vs. 28.3 +/- 1.2 h for GnRH, activin, and control, respectively), although the time course for stimulation by GnRH and activin appeared to differ. Inclusion of activin in cultures did not affect homologous stimulation of GnRH receptor synthesis. The stimulatory effects of activin were unaffected by combined treatment with inhibin (t1/2 of synthesis 17.2 +/- 2.0 h). Together, these data indicate that activin stimulates GnRH receptor synthesis in cell culture through a distinct mechanism from GnRH. Additionally, inhibin did not antagonize the stimulatory effects of activin on synthesis of GnRH receptors. This is, to our knowledge, the first demonstration of an action of activin-A on GnRH receptor synthesis.

Activins↗

PubMed1992

Regulation of production of activin A in human marrow stromal cells and monocytes.

In studies of the regulation of hematopoiesis, increasing attention has focused on the role of bone marrow stromal cells as rich sources of various cytokines. Present studies indicate that marrow stromal cells and monocytes produce activin A, implicating this new cytokine in the paracrine control of hematopoiesis. Activin A, which was initially recognized as a beta A beta A dimeric gonadal protein, was found to potentiate the proliferation and differentiation of erythroid progenitors; both purified erythroid colony-forming units (CFU-E) and K562 cells possess high affinity receptors specific for activin A. Present studies using Western and Northern blots demonstrate the presence of beta A subunits of activin A in the conditioned medium of monocytes and stromal cells and its RNA transcripts in these cells. The presence of functional and homodimeric beta A beta A activin molecule was confirmed through bioassay with or without a blocking antiserum against activin A or an activin binding protein, follistatin; its presence is further supported by a specific enzyme-linked immunosorbent assay (ELISA) in which a monoclonal antibody reacted only with the beta A beta A dimeric form of this molecule. In other experiments, the production of activin A was found to be regulated by various cytokines and regulators. The production of activin A in monocytes was stimulated more than ninefold by treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). Activin A expression was also stimulated, albeit less potently, by bacterial lipopolysaccharide (LPS) and gamma-interferon. On the other hand, the expression of activin A in marrow stromal cells was upregulated by incubation with tumor necrosis factor-alpha (TNF-alpha), LPS, and interleukin 1 alpha (IL-1 alpha). Therefore, we propose that the local production of activin A in the microenvironment within bone marrow may fine tune the regulation of steady-state hematopoiesis. In addition, this factor may normally be produced at minimal levels, but under certain situations may be further induced to provide important biological functions.

Activins↗

PubMed1992

Specific erythroid differentiation of mouse erythroleukemia cells by activins and its enhancement by retinoic acids.

Activin A has been shown to induce hemoglobin production in various hematopoietic cells. Such activities of three structurally distinct activins (activin A, activin AB, and activin B) were compared using F5-5 mouse erythroleukemia cells. Activin A and AB had similarly potent inducing activities whereas that of activin B was much lower. The erythroid inducing activity of activins was suppressed by follistatin, an activin-binding protein but not by inhibin A and inhibin B. Retinoic acids (both all-trans and 13-cis) had weak erythroid differentiation activity. In addition, clear synergistic erythroid induction occurred when retinoic acid and activin A were mixed together. These results indicate that retinoic acid may modulate activin-induced erythropoiesis in vivo.

Activins↗

PubMed1989

Stimulation of glucose production by activin-A in isolated rat hepatocytes.

The effect of activin-A on glycogenolysis was studied in isolated rat hepatocytes. Activin-A stimulated glucose output in hepatocytes in a dose-dependent manner. The maximal effect of the glycogenolytic action of activin-A, which was about 50% of the glucagon action, was obtained at 10(-9) M. When 10(-9) M activin-A and 5 x 10(-9) M glucagon were added simultaneously, the actions of these two agents were additive. In contrast, there was no additivity when 10(-9) M activin-A and 10(-8) M angiotensin-II were added. Activin-A did not increase cAMP at any doses tested, but induced a rapid increase in cytoplasmic free calcium concentration. Activin-A increased the cytoplasmic free calcium concentration even in the presence of 1 microM extracellular calcium, suggesting that activin-A caused calcium release from an intracellular calcium pool(s). The internal calcium pool affected by activin-A appeared to be the same as that affected by either angiotensin-II or vasopressin. When [3H] inositol-labeled hepatocytes were incubated with activin-A, radioactivity in the inositol trisphosphate fraction was rapidly increased. These results indicate that activin-A acts on rat hepatocytes and stimulates glycogenolysis by activating the calcium messenger system.

Activins↗

PubMed1990

Activin-A inhibits oxytocin and progesterone production by preovulatory bovine granulosa cells in vitro.

The aim was to examine the effect of activin on luteinization of preovulatory bovine granulosa cells in vitro. Bovine activin-A was found to inhibit the production of oxytocin (OT) and progesterone by bovine granulosa cells from individual preovulatory follicles cultured in serum-free medium. The minimal response on OT production (25% inhibition) occurred with 0.1-1 ng/ml activin-A, and the maximal inhibition (83%) occurred with 10 ng/ml activin-A after 2-3 days in culture. Progesterone showed a similar response (30% inhibition for 0.1-1 ng/ml and 74% for 10 ng/ml). Inhibin production was not consistently effected by activin-A. Inhibin (75 U/ml) had no detectable effect upon OT or progesterone production. When activin-A was withdrawn from the cell culture after 72 h and the incubation continued for a further 72 h, a recovery in OT was seen on day 4 and 5 after activin-A doses of 0.1-1 ng/ml, but not after higher doses (3 and 10 ng/ml). Progesterone did not show a recovery, but the levels remained constant for 3 days (0.1 and 0.3 ng/ml activin-A) or for 1 day (1-10 ng/ml activin-A) and then fell to control levels by day 6 of culture. We conclude that bovine activin-A has an autocrine action on bovine granulosa cells in vitro, to inhibit basal production of OT and progesterone, consistent with the role of activin-A in delaying the process of luteinization.

Activins↗

PubMed1990

Activin stimulates spermatogonial proliferation in germ-Sertoli cell cocultures from immature rat testis.

Activin and inhibin are peptide hormones produced in the gonads which may act as autocrine and/or paracrine regulators of testicular function. Sertoli cells produce inhibin, and it has recently been shown that Leydig cells can produce activin in vitro. To further explore the local actions of activin and inhibin in the testis, Sertoli and germ cells were isolated from immature rats and cocultured in vitro. In these cultures we demonstrate that activin A and activin B, but not inhibin A, stimulated spermatogonial proliferation in vitro. Activin increased [3H]thymidine incorporation 2- to 4-fold in cocultures after 48-72 h of treatment. Using autoradiography, the label was localized in the clusters of spermatogonia adhering to the Sertoli cell monolayer. Additionally, activin stimulated a reaggregation of the cultures into tubule-like structures. Fluorescence-activated cytometry was used to analyze the cell population based on size, DNA content, and lipid content. Sertoli cells were identified using Nile Red staining of intracellular lipid droplets; spermatogonia are Nile Red-negative. Activin treatment caused a marked increase in the fraction of Nile Red-negative cells in the cocultures. Activin also caused an increase in the percentage of these cells having 4C DNA. Lastly, specific binding of activin A to 2C, but not 4C, germ cells was demonstrated. These data demonstrate that activin acts as a regulator of spermatogonial proliferation in the male.

Activins↗

PubMed1991

Evidence for an autocrine role of activin B within rat anterior pituitary cultures.

Activins, dimers of inhibin beta subunits, are potent stimulators of FSH secretion in vivo and in vitro and of FSH beta mRNA expression in rat anterior pituitary cultures. In this study, we investigated the possibility that locally secreted activin B (beta B beta B) may function as an autocrine modulator of basal FSH secretion and expression based on the previous observation that beta B is expressed within gonadotropes. The incubation of cultured rat anterior pituitary cells with a m mouse monoclonal antibody specific for the activin B homodimer (MAb-activin B) significantly attenuated the basal secretion of FSH in a concentration- and time-dependent manner, without influencing LH secretion. Moreover, MAb-activin B selectively inhibited FSH beta mRNA accumulation without affecting either LH beta or alpha subunit mRNAs. The MAb-activin B completely blocked the stimulation of FSH secretion by exogenous activin B, but not by activin A, confirming its specificity. As previously shown, inhibin A and follistatin significantly suppressed basal FSH secretion in these cultures. This inhibitory effect, albeit of lower magnitude, was still evident even in the presence of the MAb-activin B which by itself suppressed basal FSH secretion. These data suggest that the secretion of activin B by the gonadotropes of the anterior pituitary may serve as an autocrine signal in the selective modulation of FSH expression and secretion. Furthermore, the inhibitory actions of inhibins and follistatins on gonadotropes may, in part, be explained by their ability to interfere with the actions of endogenous activin B.

Activins↗

PubMed1992

Activin-binding proteins in human serum and follicular fluid.

Binding proteins that transport and/or modify the biological action of peptide hormones and growth factors have been identified for an increasing number of endocrinologically important substances. Since these binding proteins can mask epitopes critical for recognition in immunoassays and can neutralize the bioactivity of their targets, elucidation of hormonal physiology can be intricately tied to analysis of binding protein structure and function. Therefore, we investigated whether circulating activin- and inhibin-binding proteins exist in human serum by incubating purified recombinant human 125I-activin with serum samples. After gel permeation chromatography, radioactive activin was identified in three peaks, a high molecular wt (mol wt) binding protein peak (230 kDa), a lower mol wt binding protein peak (60 kDa), and free activin (22.5 kDa). Bound activin was displaced from the lower mol wt binding protein with either activin or inhibin, but was not displaced from the high mol wt peak with a 10-fold greater concentration of activin. Since an activin-binding protein, follistatin, has been identified in ovarian and pituitary extracts, these same analytical techniques were applied to analysis of human follicular fluid as well. A large, 60 kDa binding protein peak eluting in a position similar to the lower mol wt peak in serum was observed, consistent with this protein being follistatin. These results demonstrate the presence of at least two activin-binding proteins, distinguishable by size, in human serum that may interfere with attempts to assay activin levels in circulation without prior extraction, and may also be involved in regulating the biological actions of activin.

Activins↗