Glucocortıcoıds: As A Clınıcıan We Use Much, We Know Less

Year 2009, Volume: 26 Issue: 3, 102 - 106, 22.12.2010

Alişan Yıldıran , Aynur Düzgün Recep Sancak

Abstract

Glucocorticoids (GC) are frequently used important drugs in clinical practice of pediatrics. As well as, they have important physiologic functions; they have immune suppressive, anti-inflammatory and anti-allergic effects that they exert on primary and secondary immune cells, tissues and organs. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGR); secondary non-genomic effects which are also initiated by the cGR; membrane-bound glucocorticoid receptor (mGR)-mediated non-genomic effects and finally non-specific, non-genomic effects caused by interactions with cellular membranes. Mechanisms of GR action are transactivation (GR binds to a related element in the promoter region of GC sensitive genes, inducing gene transcription) and transrepression (GR binds to a negative related element in a promoter region of GC-regulated genes that inhibit gene transcription by interfering with the binding of activating transcription factors). The underlying molecular mechanisms for their side effects are complex and frequently only partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma), whereas others are predominantly mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). In this review, we aimed to look at new molecular mechanisms of effects and side effects in relationship with apoptosis and caveolin, intracellular transport and endoplasmic reticulum stress, resistance mechanisms and new drugs developed based on these topics of GCs.

Keywords

Glucocorticoids, Apoptosis, Caveolins, Genomics, Mechanisms, New

References

• Aridor, M., Hannan, L.A., 2000. Traffic jam: A compendium of human diseases that affect intracellular transport processes. Traffic. 1, 836-851.
• Barnes, P.J., Adcock, I.M., 2009. Glucocorticoid resistance in inflammatory diseases. Lancet. 373, 1905-1917.
• Buttgereit, F., Straub, R.H., Wehling, M., Burmester, G.R., 2004. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 50, 3408-3417.
• Buttgereit, F., Burmester, G.R., Lipworth, B.J., 2005. Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet. 365, 801-803.
• Dirks-Naylor, A.J., Griffiths, C.L., 2009. Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy. J. Steroid. Biochem. Mol. Bio. 117, 1-7.
• Frankfurt, O., Rosen, S.T., 2004. Mechanism of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr. Op. Oncol. 16, 553-563.
• Fujii, Y., Khoshnoodi, J., Takenaka, H., Hosoyamada, M., Nakajo, A., Bessho, F., Kudo, A., Takahashi, S., Arimura, Y., Yamada, A., Nagasawa, T., Ruotsalainen, V., Tryggvason, K., Lee, A.S., Yan, K., 2006. The effect of dexamethasone on defective neprin transport caused by ER stress: A potential mechanism for the therapeutic action of glucocorticoids in the acquired glomerular diseases. Kidney Int., 69, 1350-1359.
• Hersey, P., Zhang, X.D., 2009. Treatment combinations targeting apoptosis to improve immunotherapy of melanoma. Cancer Immunol. Immunother. 58, 1749-1759.
• Gass, J.R., Jiang, H.Y., Wek, R.C., Brewer, J.W., 2008. The unfolded protein response of B-lymphocytes: PERK- independent development of antibody-secreting cells. Mol. Immunol., 45, 1035-1043.
• Kim, R., Emi, M., Tanabe, K., Murakami, S., 2006. Role of the unfolded protein response in cell death. Apoptosis. 11, 5-13.
• Löwenberg, M., Verhaar, A.P., Van Den Brink, G.R., Hommes, D.W., 2007. Glucocorticoid signallig: a nongenomic mechanism for T-cell immunosupression. Trends Mol. Med. 13, 158-163.
• Ma, T., Han, L., Gao, Y., Li, L., Shang, X., Hu, W., Xue, C., 2008. The endoplasmic reticulum stress-mediated apoptosis signal pathway is involved in sepsis-induced abnormal lymphocyte apoptosis. Eur. Surg. Res., 41, 219-225.
• Matthews, L., Berry, A., Ohanian, J., Garside, H., Ray, D., 2008. Caveolin mediates rapid glucocorticoid effects and couples glucocorticoid action to the antiproliferative program. Mol. Endocrin. 22, 1320-1330.
• Rutkowski, D.T., Kaufman, R.J., 2007. That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem. Sci. 32, 469-476.
• Shäcke, H., Berger, M., Rehwinkel, H., Asadullah, K., 2007. Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index. Mol. Cell Endoc. 275, 109-117.
• Schäcke, H., Döcke, W.D., Asadullah, K., 2002. Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Therapeutics. 96, 23-43.
• Schroder, M., Kaufman, R.J., 2005. ER stress and the unfolded protein response. Mutation Res. 569, 29-63.
• Stahn, C., Löwenberg, M., Hommes, D.W., Buttgereit, F., 2007. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol. Cell Endocrin. 275, 71-78.
• Thompson, E.B., 2008. Stepping stones in the path of glucocorticoid-driven apoptosis of lymphoid cells. Acta. Biochim. Biophys. Sin. 40, 595-600.