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Regulation by Glucocorticosteroids (Prostanoid/Corticotropin/Cortisol/Inhibition) MURRAY D

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Regulation by Glucocorticosteroids (Prostanoid/Corticotropin/Cortisol/Inhibition) MURRAY D Proc. Natl. Acad. Sci. USA Vol. 79, pp. 7547-7551, December 1982 Medical Sciences Prostaglandin biosynthesis in the human fetal adrenal gland: Regulation by glucocorticosteroids (prostanoid/corticotropin/cortisol/inhibition) MURRAY D. MITCHELL*tt, BRUCE R. CARR*t, J. IAN MASON*tt, AND EVAN R. SIMPSON*tt *The Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Departments of tBiochemistry and tObstetrics and Gynecology, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235 Communicated by Ralph T. Holman, September 13, 1982 ABSTRACT Human fetal adrenal (HFA) tissue was main- steroid secretion by the adrenal gland by way ofa mechanism(s) tained in organ culture to evaluate the biosynthesis ofprostaglan- that involves activation or inhibition of adenylate cyclase (10- dins and hormonal regulation of prostaglandin formation by this 12). Hence, it seemed reasonable that PGs synthesized in situ tissue. The HFAtissue secreted substantial amounts ofprostaglan- might act as mediators or modulators ofcorticotropin action on din E2, prostaglandin F2, 13,14-dihydro-15-ketoprostaglandin the HFA. PG synthesis by the HFA, however, has not been F2a, 6-ketoprostaglandin Fl., and thromboxane B2; secretion of described. Yet several lines of evidence support a role for the prostaglandin D2 could not be demonstrated. Prostaglandin bio- HFA as a source ofPGs. For example, PGs are present in fetal synthesis in HFA tissue was inhibited in a time-dependent manner plasma and concentrations increase with gestational age (13). by corticotropin (ACTH; 0.4 PM); by the fourth day of culture, Moreover, under conditions in which the human fetal adrenal the extent of inhibition of biosynthesis of each prostaglandin was has atrophied, such as fetal anencephaly, there is circumstantial 60-90%. Progesterone (1 PLM), cortisol (1 /AM), and dexametha- sone (1 atM) inhibited prostaglandin biosynthesis whereas estra- evidence that fetal production of PGs is greatly reduced, as diol (1 ,IM) did not. Ofthe compounds tested for inhibitory activ- shown by undetectable levels in amniotic fluid (14). In addition, ity, dexamethasone was the most potent. An inhibitor of 11g3- the rapid involution of the fetal zone of the HFA suggests an hydroxylase activity (metyrapone; 0.1 mM) effectively eliminated acute change in vascular tone that results in reduced blood flow the inhibition of prostaglandin biosynthesis caused by corticotro- to the cells of the fetal zone, an event that may be due to an pin and progesterone. Metyrapone treatment alone caused a 3- alteration in local PG synthesis. A similar explanation has been fold increase in prostaglandin biosynthesis byfetal adrenal tissues. invoked to account for the closure of umbilical vessels at birth Similar stimulatory effects resulted from treatmentwith inhibitors (15). of(i) 33-hydroxysteroid dehydrogenase (cyanoketone; 15 IAM), (ii) To test the hypotheses that HFA tissue synthesizes PGs and steroid 17a-hydroxylase (SU 10603; 19 jLM), and (iii) cholesterol that corticotropin may influence the rate of PG synthesis, we side-chain cleavage (aminoglutethimide; 1 mM). Inhibition of maintained HFA tissue in organ culture (6) and investigated PG prostaglandin biosynthesis by dexamethasone in the presence or biosynthesis by the tissue in the absence and presence of cor- absence ofmetyrapone was concentration dependent and 50% in- ticotropin. We found that corticotropin treatment of HFA tissue hibition could be demonstrated at 1 nM. A competitive inhibitor caused a time-dependent inhibition of PG biosynthesis. The of the binding of glucocorticosteroids to cytoplasmic receptors findings ofa detailed study ofthis phenomenon are presented. (cortisol 21-mesylate; 1 FIM) significantly reduced the inhibition ofprostaglandin biosynthesis effected by dexamethasone (10 nM). These findings suggest that prostaglandin biosynthesis in the HFA MATERIALS AND METHODS gland is regulated by endogenously synthesized glucocorticoste- Source of Tissue. Human fetal adrenal glands were obtained roids, the actions of which are mediated by a glucocorticosteroid from first and second trimester abortuses; abortions were ac- receptor. Such glucocorticosteroids induce the synthesis ofa sub- complished by dilatation and extraction. Tissues were obtained stance that inhibits prostaglandin biosynthesis. in accordance with the Donors Anatomical Gift Act of the State of Texas after obtaining written consent from the women to be In most, ifnot all, mammalian species, the fetal adrenal glands aborted by using a consent form and protocol approved by the serve an important role in the maturational processes that en- Human Research Review Committee ofthe University ofTexas sure the timely birth ofa viable fetus (1). An understanding of Health Science Center at Dallas. the regulation of hormone secretion by the human fetal adrenal Preparation and Culture of Tissue. Within 1 hr of fetal (HFA) gland is therefore ofsignal importance to understanding death, the adrenal glands were removed and minced into pieces the development of the human fetus. The HFA gland at term of approximately 1 mm3. Four fragments of adrenal tissue (ap- can secrete up to 200 mg of steroids daily (2, 3); the principal proximately 1 mg oftissue protein) were placed on a lens paper product is dehydroisoandrosterone sulfate, although significant supported by a stainless steel grid in each organ culture dish quantities ofcortisol also are produced (4-6). In rat adrenocor- (60 X 15 mm; Falcon Plastics, Cockeysville, MD). The medium tical cells, corticotropin (ACTH) causes the hydrolysis of cho- used consisted of 50 vol of Waymouth's MB 752/1 medium, lesterol esters, resulting in increased availability ofprecursors 40 vol of Gey's balanced salt solution (GIBCO), 1 vol of a 1% for prostaglandin (PG) biosynthesis (7). It has been shown that solution ofantibiotics and antimycotics (GIBCO), and 10 vol of PGs act to modulate steroid secretion by adult human adrenal whole human serum (6). The medium (1 ml) was changed every gland tissue (8) and in particular HFA tissue (9). There is ap- 24 hr for 4 days and stored at -200C. At the end ofthe culture preciable evidence that corticotropin and PGs act to modify period, the tissue fragments were rinsed thoroughly and ho- mogenized in 0.5 ml of0.15 M sodium chloride. Aliquots ofthe The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertise- Abbreviations: HFA, human fetal adrenal; PG, prostaglandin; PGE2, ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. PGF2,, etc., PG E2, PG F2<,, etc.; TXB2, thromboxane B2. 7547 Downloaded by guest on September 27, 2021 7548 Medical Sciences: Mitchell et al. Proc. Natl. Acad. Sci. USA 79 (1982) homogenates were taken for measurement of protein by the method described by Lowry et al. (16). Each experimental condition was replicated in quadruplicate or quintuplicate. Results are expressed as pg of PG secreted into 1,500 F the WI culture medium per mg of tissue protein per 24 hr (mean o._ ± SEM). c0 - i Materials. Synthetic ACTH1_24 (Cortrosyn) was obtained ,oc from Organon (W. Orange, NJ). Progesterone, a._ 1,000 - 170-estradiol, 0& 1r, I cortisol, and dexamethasone were obtained from Sigma. Me- .20 'c tyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone) was pur- U) _ chased from Aldrich. Aminoglutethimide and SU 10603 [7- _L chloro-3,4-dihydro-2-(3-pyridyl)-napthalen-1-one] were pro- o o% 500 - vided by Ciba-Geigy. Cyanoketone (2a-cyano-4,4, 17a-trimeth- yl-17,B3hydroxyandrost-5-en-3-one) was a gift of Sterling Win- throp (Rensselaer, NY), and cortisol 21-mesylate was a gift of S. Stoney Simons, Jr., National Institute ofArthritis, Diabetes and Digestive and Kidney Diseases. 0 Measurements ofPGs. PGs were measured by sensitive and PGE2 PGF2a PGFM 6KF1a TXB2 specific radioimmunoassays that have been fully described and FIG. 1. Effect of corticotropinj_24 on rates of production of pro- validated elsewhere (17-19). The PGs measured were PGE2, stanoidsby HFA tissue. Fragments of HFA tissue maintained in organ PGF2a, 13,14-dihydro-15-keto-PGF2. (PGFM, a major metab- culture were incubated in medium containing whole human serum olite of PGF2.), PGD2, and 6-keto-PGFia, the degradation alone (EC) or in medium containingwhole human serumand4 jAM corti- product of prostacyclin. Thromboxane B2 (TXB2, the degrada- cotropinl_2A (E0). The media were changed every 24 hr and prostanoids tion product of thromboxane A2) was also measured (20). The were assayed in the media collected on the fourth day of culture. Re- lower limits of sensitivity of the assays are in the range 1-5 pg sults represent mean ± SEM of values obtained from media of four per tube and intra-assay coefficients of variation are less than replicate dishes. 6KFa, 6-keto-PGF1I. 10%. Crossreactivities of the antisera with the other PGs mea- HFA tissue to convert to such a steroid. Cortisol seemed a log- sured are less than 1%. ical candidate for this steroid since cortisol is known to inhibit PG biosynthesis in certain other tissues (21, 22). Hence, we RESULTS investigated the effects of cortisol and dexamethasone on PG production by HFA tissue and the effects of two inhibitors of HFA tissue was maintained in organ culture for 4 days in the steroid biosynthesis (23)-i.e., an inhibitor of steroid 17a-hy- absence or presence of corticotropin (0.4 ,uM). In the absence droxylase activity (SU 10603) and an inhibitor of 3/-hydroxy- ofcorticotropin, the tissue secreted a variety of PGs and TXB2 steroid dehydrogenase activity (cyanoketone). The results are throughout the 4-day period. Secretion ofPGD2 by HFA tissue shown in Fig. 3. Inhibition of steroid biosynthesis resulted in could not be detected. Corticotropin inhibited the biosynthesis 3- to 4-fold stimulation of the rate of PG biosynthesis, sug- of all PGs and TXB2 with maximal inhibition occurring on the later days of culture; the rates of synthesis on the final day of 150 culture are shown in Fig.
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