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      The Glucocorticoid Receptor: A Revisited Target for Toxins

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          Abstract

          The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.

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          Most cited references167

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          Glucocorticoid resistance in inflammatory diseases.

          Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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            Nuclear hormone receptors and gene expression.

            The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different "orphan" receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by "cross-talking" to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compactation and transcriptional repression. Upon ligand binding, the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.
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              Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor.

              Anthrax lethal toxin, produced by the bacterium Bacillus anthracis, is the major cause of death in animals infected with anthrax. One component of this toxin, lethal factor (LF), is suspected to be a metalloprotease, but no physiological substrates have been identified. Here it is shown that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway. The identification of a cleavage site for LF may facilitate the development of LF inhibitors.
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                Author and article information

                Journal
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                09 June 2010
                June 2010
                : 2
                : 6
                : 1357-1380
                Affiliations
                [1 ]Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, 201 DHLRI, 473 W. 12th Avenue, Columbus, OH 43210, USA
                [2 ]Institute for Behavioral Medicine Research, The Ohio State University Medical Center, 460 Medical Center Drive, Columbus, OH 43210, USA
                [3 ]Department of Health and Human Services, Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, 5625 Fishers Lane, Rm. 4N13 (MSC 9401), Bethesda, MD 20892-9401, USA; Email: sternbee@ 123456mail.nih.gov
                Author notes
                [* ] Author to whom correspondence should be addressed; Email: jeanette.marketon@ 123456osumc.edu ; Tel.: +1-614-293-3496; Fax: +1-614-366-2074.
                Article
                toxins-02-01357
                10.3390/toxins2061357
                3153245
                22069642
                40018a36-9da3-4b76-a8fc-59a08c39db61
                © 2010 by the authors; licensee MDPI, Basel, Switzerland

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 15 May 2010
                : 28 May 2010
                : 07 June 2010
                Categories
                Review

                Molecular medicine
                glucocorticoid receptor,toxins,anthrax lethal toxin,bacterial toxins,environmental toxins

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