Glucocorticoids are potent immunosuppressants which work in part by inhibiting cytokine gene transcription. We show here that NF-B, an important regulator of numerous cytokine genes, is functionally inhibited by the synthetic glucocorticoid dexamethasone (DEX). In transfection experiments, DEX treatment in the presence of cotransfected glucocorticoid receptor (GR) inhibits NF-B p65-mediated gene expression and p65 inhibits GR activation of a glucocorticoid response element. Evidence is presented for a direct interaction between GR and the NF-B subunits p65 and p50. In addition, we demonstrate that the ability of p65, p50, and c-rel subunits to bind DNA is inhibited by DEX and GR. In HeLa cells, DEX activation of endogenous GR is sufficient to block tumor necrosis factor alpha or interleukin 1 activation of NF-B at the levels of both DNA binding and transcriptional activation. DEX treatment of HeLa cells also results in a significant loss of nuclear p65 and a slight increase in cytoplasmic p65. These data reveal a second mechanism by which NF-B activity may be regulated by DEX. We also report that RU486 treatment of wild-type GR and DEX treatment of a transactivation mutant of GR each can significantly inhibit p65 activity. In addition, we found that the zinc finger domain of GR is necessary for the inhibition of p65. This domain is also required for GR repression of AP-1. Surprisingly, while both AP-1 and NF-B can be inhibited by activated GR, synergistic NF-B/AP-1 activity is largely unaffected. These data suggest that NF-B, AP-1, and GR interact in a complex regulatory network to modulate gene expression and that cross-coupling of NF-B and GR plays an important role in glucocorticoid-mediated repression of cytokine transcription.Glucocorticoids have long been used as effective immunosuppressive agents in the treatment of conditions involving T-cell-or cytokine-mediated tissue damage. These steroids have been shown to block inflammation, suppress immune system activation, and act as growth-inhibitory agents both in vivo and in vitro (23). Surprisingly, despite the lengthy history of the use of glucocorticoids as therapeutic agents, the mechanism by which they perform these functions is largely unknown.Studies of the effect of glucocorticoid administration on the immune system have resulted in a number of important observations. Glucocorticoids induce a rapid redistribution of lymphocytes from the circulation to other lymphoid compartments (23). In addition, glucocorticoids potently suppress lymphocyte accessory function, the clonal expansion of T lymphocytes, and the secretion of cytokines (23, 73). Interestingly, cytotoxic Tlymphocyte clones provided with exogenous interleukin 2 (IL-2) are able to proliferate in response to mitogenic stimulation in the presence of glucocorticoids (28). These data suggest that the block of cytokine secretion plays an important role in glucocorticoid-mediated immunosuppression. Indeed, glucocorticoid administration represses the de novo transcription of a number of cytokine gene...

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A common event that occurs during apoptosis is a loss of cell volume, but little information is available on its role in the cell death process. Lymphocytes undergo apoptosis in response to glucocorticoids and exhibit cell shrinkage, nuclear condensation, internucleosomal DNA fragmentation, and apoptotic body formation. Interestingly, only cells that exhibit a loss in cell volume degrade their DNA. To determine if physical shrinkage was sufficient to initiate apoptosis, S49 Neo lymphocytes were cultured in hypertonic medium. The normal osmolarity (approximately 300 mosM) of tissue culture medium was increased to either 550 or 800 mosM, using impermeant sugars such as mannitol and sucrose or NaCl. These hypertonic conditions led to a rapid killing of S49 Neo cells. Evaluation of the mode of cell death revealed that these hypertonic conditions resulted in apoptosis. Unlike glucocorticoid-induced cell death, hypertonically induced apoptosis did not require protein synthesis. When S49 Neo cells were cultured under hypotonic conditions, the cells swelled but apoptosis did not occur. Analysis of several cell types revealed that all lymphoid cells examined (S49 Neo, CEM-C7, primary thymocytes) undergo apoptosis in response to hypertonic conditions, whereas several other cell types (L cells, COS, HeLa, GH3) did not. Although these nonlymphoid cells showed a similar initial reduction in cell volume in response to hypertonic conditions, they subsequently maintained volume or regulated back to a near normal cell volume. These data indicate that thymic lymphoid cells have the machinery in place for rapid induction of apoptosis in response to physical shrinkage, whereas other cell types resist shrinkage-induced apoptosis by the activation of cell volume regulatory mechanisms.

The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate. S101 Parathyroid hormone receptors S101 Platelet-activating factor receptor S102 Prokineticin receptors S103 Prolactin-releasing peptide receptor S104 Prostanoid receptors S106 Proteinase-activated receptors S107 QRFP receptor S108 Relaxin family peptide receptors S110 Somatostatin receptors S111 Succinate receptor S111 Tachykinin receptors S113 Thyrotropin-releasing hormone receptors S113 Trace amine receptor S114 Urotensin receptor S115 Vasopressin and oxytocin receptors S117 VIP and PACAP receptors S130 Ligand-gated ion channels S131 5-HT 3 receptors S133 Acid-sensing (proton-gated) ion channels (ASICs) S135 Epithelial sodium channels (ENaC) S137 GABA A receptors S142 Glycine receptors S145 Ionotropic glutamate receptors S150 IP 3 receptor S151 Nicotinic acetylcholine receptors S154 P2X receptors S156 ZAC S160 Voltage-gated ion channels S161 CatSper and Two-Pore channels S163 Cyclic nucleotide-regulated channels S164 Potassium channels S165 Calcium-and sodium-activated potassium channels S166 Inwardly rectifying potassium channels S169 Two P domain potassium channels S171 Voltage-gated potassium channels S175 Ryanodine receptor S176 Transient Receptor Potential channels S186 Voltage-gated calcium channels S189 Voltage-...