Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1983 May;40(2):613–621. doi: 10.1128/iai.40.2.613-621.1983

Down regulation of hepatic glucocorticoid receptors after endotoxin treatment.

R D Stith, R E McCallum
PMCID: PMC264898  PMID: 6840856

Abstract

The mechanism by which endotoxin administration results in hypoglycemia was evaluated by characterizing [3H]dexamethasone binding and phosphoenolpyruvate carboxykinase activity in hepatic cytosol preparations from treated and control mice. Starved mice were given Escherichia coli O111:B4 endotoxin or saline intraperitoneally on day 3 after bilateral adrenalectomy. [3H]dexamethasone binding was measured by the charcoal method after the incubation of cytosol preparations with [3H]dexamethasone in the presence or absence of unlabeled dexamethasone. Changes in [3H]dexamethasone binding were found to be time and dose dependent in treated mice. When mice given different doses of endotoxin reached the same stage of morbidity, as indicated by the average time of death, significantly lower glucocorticoid binding was measured. Scatchard analysis of binding isotherms defined a single class of binding sites. Association and dissociation rate constants and the equilibrium dissociation constant (Kd) were not altered, but the maximum number of binding sites was depressed by endotoxin. The rank order of potency of competitors for [3H]dexamethasone binding, dexamethasone greater than hydrocortisone = corticosterone greater than deoxycorticosterone greater than progesterone greater than testosterone = estradiol, was consistent with a glucocorticoid receptor, although the competition was not altered by endotoxin. Endotoxin treatment prevented the glucocorticoid-induced increase in hepatic phosphoenolpyruvate carboxykinase activity. We conclude that the hypoglycemia of endotoxin poisoning is effected, in part, by the inhibition of the glucocorticoid-mediated induction of phosphoenolpyruvate carboxykinase via the down regulation of hepatic glucocorticoid receptors.

Full text

PDF
613

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ash J. F., Singer S. J. Concanavalin-A-induced transmembrane linkage of concanavalin A surface receptors to intracellular myosin-containing filaments. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4575–4579. doi: 10.1073/pnas.73.12.4575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berry L. J. Bacterial toxins. CRC Crit Rev Toxicol. 1977 Nov;5(3):239–318. doi: 10.3109/10408447709082601. [DOI] [PubMed] [Google Scholar]
  3. Bradley S. G. Cellular and molecular mechanisms of action of bacterial endotoxins. Annu Rev Microbiol. 1979;33:67–94. doi: 10.1146/annurev.mi.33.100179.000435. [DOI] [PubMed] [Google Scholar]
  4. Catt K. J., Harwood J. P., Aguilera G., Dufau M. L. Hormonal regulation of peptide receptors and target cell responses. Nature. 1979 Jul 12;280(5718):109–116. doi: 10.1038/280109a0. [DOI] [PubMed] [Google Scholar]
  5. Chang H. C., Lane M. D. The enzymatic carboxylation of phosphoenolpyruvate. II. Purification and properties of liver mitochondrial phosphoenolpyruvate carboxykinase. J Biol Chem. 1966 May 25;241(10):2413–2420. [PubMed] [Google Scholar]
  6. Exton J. H. Gluconeogenesis. Metabolism. 1972 Oct;21(10):945–990. doi: 10.1016/0026-0495(72)90028-5. [DOI] [PubMed] [Google Scholar]
  7. Gartner S. L. Hepatic levels of cyclic AMP in normal and lead-sensitized rats after treatment with bacterial endotoxin. Experientia. 1975 May 15;31(5):566–567. doi: 10.1007/BF01932461. [DOI] [PubMed] [Google Scholar]
  8. Geiger B., Singer S. J. The participation of alpha-actinin in the capping of cell membrane components. Cell. 1979 Jan;16(1):213–222. doi: 10.1016/0092-8674(79)90202-2. [DOI] [PubMed] [Google Scholar]
  9. Giger O., McCallum R. E. Response of mouse liver glycogen cycle enzymes to endotoxin treatment. Am J Physiol. 1976 Oct;231(4):1285–1289. doi: 10.1152/ajplegacy.1976.231.4.1285. [DOI] [PubMed] [Google Scholar]
  10. Hartree E. F. Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal Biochem. 1972 Aug;48(2):422–427. doi: 10.1016/0003-2697(72)90094-2. [DOI] [PubMed] [Google Scholar]
  11. Hollenberg M. D. Hormone receptor interactions at the cell membrane. Pharmacol Rev. 1978 Dec;30(4):393–410. [PubMed] [Google Scholar]
  12. Klotz I. M. Numbers of receptor sites from Scatchard graphs: facts and fantasies. Science. 1982 Sep 24;217(4566):1247–1249. doi: 10.1126/science.6287580. [DOI] [PubMed] [Google Scholar]
  13. McCallum R. E., Seale T. W., Stith R. D. Influence of endotoxin treatment on dexamethasone induction of hepatic phosphoenolpyruvate carboxykinase. Infect Immun. 1983 Jan;39(1):213–219. doi: 10.1128/iai.39.1.213-219.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McCallum R. E., Stith R. D. Endotoxin-induced inhibition of steroid binding by mouse liver cytosol. Circ Shock. 1982;9(4):357–367. [PubMed] [Google Scholar]
  15. McGinnis J. F., de Vellis J. Cell surface modulation of gene expression in brain cells by down regulation of glucocorticoid receptors. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1288–1292. doi: 10.1073/pnas.78.2.1288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Melby J. C. Clinical pharmacology of systemic corticosteroids. Annu Rev Pharmacol Toxicol. 1977;17:511–527. doi: 10.1146/annurev.pa.17.040177.002455. [DOI] [PubMed] [Google Scholar]
  17. Mirás M. E., Harrison R. W. Characteristics of glucocorticoid binding to mouse liver cytosol. J Steroid Biochem. 1979 Aug;11(2):1129–1134. doi: 10.1016/0022-4731(79)90163-8. [DOI] [PubMed] [Google Scholar]
  18. Nielsen C. J., Sando J. J., Pratt W. B. Evidence that dephosphorylation inactivates glucocorticoid receptors. Proc Natl Acad Sci U S A. 1977 Apr;74(4):1398–1402. doi: 10.1073/pnas.74.4.1398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pieroni R. E., Levine L. Enhancing effect of insulin on endotoxin lethality. Experientia. 1969 May 15;25(5):507–508. doi: 10.1007/BF01900787. [DOI] [PubMed] [Google Scholar]
  20. Rippe D. F., Berry L. J. Immunological quantitation of hepatic tryptophan oxygenase in endotoxin-poisoned mice. Infect Immun. 1973 Oct;8(4):534–539. doi: 10.1128/iai.8.4.534-539.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rippe D. F., Berry L. J. Study of inhibition of induction of phosphoenolpyruvate carboxykinase by endotoxin with radial immunodiffusion. Infect Immun. 1972 Nov;6(5):766–772. doi: 10.1128/iai.6.5.766-772.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rousseau G. G., Baxter J. D., Tomkins G. M. Glucocorticoid receptors: relations between steroid binding and biological effects. J Mol Biol. 1972 Jun 14;67(1):99–115. doi: 10.1016/0022-2836(72)90389-0. [DOI] [PubMed] [Google Scholar]
  23. SHRAGO E., LARDY H. A., NORDLIE R. C., FOSTER D. O. METABOLIC AND HORMONAL CONTROL OF PHOSPHOENOLPYRUVATE CARBOXYKINASE AND MALIC ENZYME IN RAT LIVER. J Biol Chem. 1963 Oct;238:3188–3192. [PubMed] [Google Scholar]
  24. Sando J. J., La Forest A. C., Pratt W. B. ATP-dependent activation of L cell glucocorticoid receptors to the steroid binding form. J Biol Chem. 1979 Jun 10;254(11):4772–4778. [PubMed] [Google Scholar]
  25. Schuler J. J., Erve P. R., Schumer W. Glucocorticoid effect on hepatic carbohydrate metabolism in the endotoxin-shocked monkey. Ann Surg. 1976 Apr;183(4):345–354. doi: 10.1097/00000658-197604000-00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sibbald W. J., Short A., Cohen M. P., Wilson R. F. Variations in adrenocortical responsiveness during severe bacterial infections. Unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg. 1977 Jul;186(1):29–33. doi: 10.1097/00000658-197707000-00005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. White G. L., Archer L. T., Beller B. K., Hinshaw L. B. Increased survival with methylprednisolone treatment in canine endotoxin shock. J Surg Res. 1978 Oct;25(4):357–364. doi: 10.1016/0022-4804(78)90131-2. [DOI] [PubMed] [Google Scholar]
  28. Williams L. T., Mullikin D., Lefkowitz R. J. Identification of alpha-adrenergic receptors in uterine smooth muscle membranes by [3H]dihydroergocryptine binding. J Biol Chem. 1976 Nov 25;251(22):6915–6923. [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES