Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF‐κB‐dependent transcription

Hofmann, Thomas G.; Hehner, Steffen P.; Bacher, Susanne; Dröge, Wulf; Schmitz, M. Lienhard

doi:10.1016/s0014-5793(98)01609-3

Cited by 52 publications

(28 citation statements)

References 25 publications

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“…Reasons for the conflicting results are most likely due to the different models being studied and the variation in drug type, dose, and exposure time. It has been shown that synthetic and natural Gc vary in their potency and effects on gene expression and apoptosis (38). Our results differ from many of these studies in that CS, a natural Gc, was administered in vivo to mice continuously for a period of 3 days, with Gc levels that were consistent with natural models of stress.…”

Section: Discussioncontrasting

confidence: 80%

Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function

Trottier

Newsted

King

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Natural glucocorticoids (Gc) produced during stress have profound effects on the immune system. It is well known that Gc induce apoptosis in precursor T and B cells, markedly altering lymphopoiesis. However, it has been noted that marrow myeloid cells expanded both in proportion and absolute numbers in the mouse after Gc exposure. Mice were implanted with a corticosterone (CS) tablet that increased serum Gc and caused atrophied thymuses, both classic signs of activation of the stress axis. Blood neutrophil counts were elevated (4.8؋), whereas lymphocyte counts declined. Flow cytometric analysis of the marrow revealed that the phenotypic distribution of the various major classes of cells was shifted by Gc exposure. As expected, marrow lymphocyte numbers declined >40% after 3 days of exposure to Gc. Conversely, in the myeloid compartment, both monocytes and granulocytes increased in number by >40%. Further, all granulocyte developmental stages showed large increases in both total number and percentage of cells. To investigate the functional capacity of mature granulocytes from Gc-treated mice, an improved granulocyte isolation method was developed. Gc exposure had little effect on the ability of granulocytes to produce superoxide or undergo chemotaxis or phagocytose bacteria. These results indicate that Gc treatment shifts bone marrow composition and provides evidence that granulocytes and their progenitors are selectively preserved under stressful conditions without losing function.granulopoiesis ͉ lymphopoiesis

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Section: Discussioncontrasting

confidence: 80%

Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function

Trottier

Newsted

King

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…NF-ĸB [42]. Recent reports have suggested that glucocorticoid-induced apoptosis in lymphocytes is mediated by repressing NF-kB-dependent transcription both in vitro [43]and in vivo [44]. We speculate that the glucocorticoids and nonsteroidal NaSal may have distinct mechanisms for their induction of apoptosis.…”

Section: Discussionmentioning

confidence: 89%

Sodium Salicylate-Induced Apoptosis of Human Peripheral Blood Eosinophils Is Independent of the Activation of c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase

Wong

Zhang²,

Lam³

et al. 2000

Int Arch Allergy Immunol

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Background: It has been shown that the inhibition of eosinophilic apoptosis is an important mechanism for the development of blood and tissue eosinophilia in allergic diseases. Considerable attention has recently been focused on the role played by different intracellular kinase cascades in the control of apoptosis. In the present study, we investigated the effect of sodium salicylate (NaSal), a nonsteroidal anti-inflammatory drug, on mitogen-activated protein kinases (MAPK) and apoptosis of human eosinophils. Methods: Human blood eosinophils were purified from buffy coat. NaSal-induced apoptosis of eosinophils was assessed by morphological changes and Annexin-V binding assay. Changes of MAPK activity upon treatment with NaSal were measured by kinase activity assay and Western blot. Results: NaSal could induce apoptosis of human blood eosinophils in a dose- and time-dependent manner. It could also activate c-Jun N-terminal kinase (JNK) and p38 MAPK but not extracellular signal-regulated protein kinase (ERK) activity within 1 h. Pretreatment of eosinophils with p38 MAPK and JNK anti-sense (AS) phosphorothioate oligodeoxynucleotides (ODN) or specific p38 MAPK inhibitor SB 203580 did not have any significant effect on NaSal-induced apoptosis. However, ERK AS ODNs could trigger the apoptosis of normal eosinophils. Conclusion: There is no direct relationship between the activation of JNK and p38 MAPK pathways and NaSal-induced apoptosis in human peripheral blood eosinophils.

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“…In this line, dissociation of glucocorticoid-dependent transactivation and transrepression may lead to the development of better tolerated drugs (20). Already several compounds have been reported to exhibit strong inhibition of NF-B but weak induction of the GRE-dependent reporter gene; however, clinical application of those compounds is still pending (33)(34)(35)(36).…”

mentioning

confidence: 99%

Functional Modulation of the Glucocorticoid Receptor and Suppression of NF-κB-dependent Transcription by Ursodeoxycholic Acid

Miura¹,

Ouchida²,

Yoshikawa³

et al. 2001

Journal of Biological Chemistry

128

104

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Ursodeoxycholic acid (UDCA) is the current mainstay of treatment for various liver diseases including primary biliary cirrhosis. UDCA acts as a bile secretagogue, cytoprotective agent, immunomodulator, and inhibitor of cellular apoptosis. Despite this cumulative evidence of the cytoprotective and immunosuppressive effects of UDCA, both the target molecule and pathway of UDCA action remain unknown. We previously described that, in the absence of glucocorticoid ligand, UDCA activates the glucocorticoid receptor (GR) into DNA binding species but does not elicit its transactivational function in a transient transfection assay. Here we further studied the molecular mechanism of UDCA action and revealed that the ligand binding domain of the GR is responsible for UDCA-dependent nuclear translocation of the GR. Indeed, we demonstrated that UDCA acts on the distinct region of the ligand binding domain when compared with the classical GR agonist dexamethasone, resulting in loss of coactivator recruitment and differential regulation of gene expression by the GR. Our data clearly indicated that UDCA, at least in part via activation of the GR, suppresses NF-B-dependent transcription through the intervention of GR-p65 interaction. Together with the established clinical safety of UDCA, we may propose that UDCA could be a prototypical compound for development of a novel and selective GR modifier. Ursodeoxycholic acid (UDCA)1 is the current mainstay of treatment for primary biliary cirrhosis, which is a chronic cholestatic liver disease characterized by the destruction of biliary epithelial cells (i.e. cholangiocytes), presumably by autoimmune mechanism(s) (1-3). This hydrophilic bile acid is reported to induce biochemical, histological, and prognostic improvement in patients with primary biliary cirrhosis in the virtual absence of adverse reactions (3). UDCA acts as a bile secretagogue and cytoprotective agent (1) and exerts diverse immunomodulatory actions in vitro: suppression of immunoglobulin, interleukin-2, interleukin-4, and interferon-␥ production from lymphocytes; attenuation of major histocompatibility complex expression on hepatocytes and cholangiocytes; increase in natural killer cell activity; and inhibition of eosinophil degranulation (1, 4 -9). Recently, it has been shown that UDCA inhibits cellular apoptosis via stabilization of the mitochondria membrane (10, 11). Despite this cumulative evidence of the cytoprotective and immunosuppressive effects of UDCA, both the target molecule and pathway of UDCA action remain unknown. The glucocorticoid receptor (GR) is a member of the nuclear receptors and an important transcriptional regulator involved in widely diverse physiological functions such as control of embryonic development, cell differentiation, and metabolic homeostasis (12, 13). Moreover, therapeutic activities of glucocorticoids are believed to inevitably be mediated by the GR (14). The nuclear receptors share several structural features (e.g. the ligand binding domain (LBD), DNA binding domain (DBD), and sev...

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Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF‐κB‐dependent transcription

Cited by 52 publications

References 25 publications

Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function

Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function

Sodium Salicylate-Induced Apoptosis of Human Peripheral Blood Eosinophils Is Independent of the Activation of c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase

Functional Modulation of the Glucocorticoid Receptor and Suppression of NF-κB-dependent Transcription by Ursodeoxycholic Acid

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