T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids

D’Elia, Michele; Patenaude, Johane; Dupras, Charles; Bernier, Jacques

doi:10.1152/ajpendo.00084.2010

Cited by 9 publications

(9 citation statements)

References 49 publications

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“…However, it is undetermined whether p38 MAPK regulates the sensitivity of structural lung tissues, such as ASM, to GC therapy. A similar role of p38 MAPK in regulating GC sensitivity has been described in mice overexpressing p38 MAPK, which have a reduced GC responsiveness to burn injury (25), or in Crohn's disease, where p38 MAPK activity is significantly increased in colonic tissues from GC-resistant patients when compared with GC-sensitive patients (26). The implication of p38 MAPK in the pathogenesis of Crohn's disease was further confirmed by the marked improvement of the disease in patients treated with p38 MAPK inhibitors (27).…”

supporting

confidence: 56%

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Bouazza

Debba-Pavard²,

Amrani³

et al. 2014

Am J Respir Cell Mol Biol

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Like many steroid receptors, the glucocorticoid (GC) receptor (GR) is a phosphoprotein. Although there are multiple phosphorylation sites critical for GR transcriptional activity (i.e., serine [S]203, S211, and S226), their respective role in driving GR functions is highly cell specific. We have recently identified protein phosphatase 5 as an essential Ser/Thr phosphatase responsible for impairing GR function via S211 dephosphorylation in airway smooth muscle (ASM) cells. Because p38 mitogen-activated protein kinase (MAPK) directly phosphorylates GR in different cell types in a stimulus-and celldependent manner, we investigated the role of p38 MAPK on GR phosphorylation and function in ASM cells. Cells were transfected with 100 nM p38 MAPK small interfering RNA or 2 mg MAPK kinase 3 expression vector (a specific kinase that directly activates p38 MAPK) in the presence or absence of fluticasone (100 nM) and/or p38 MAPK pharmacological inhibitor SB203580. We found that p38 MAPK blockade positively regulates GR nuclear translocation and GR-dependent induction of the steroid-target gene GC-induced leucine zipper in a hormone-independent manner. We also found that p38 MAPK-dependent regulation of GR functions was associated with a differential action on GR phosphorylation at S203 and S211 residues. This study demonstrated that the inactive state of GR in resting conditions is not only ensured by the absence of the GC ligand but also by p38 MAPK-dependent phosphorylation of unliganded GR at specific residues, which appears to be important in determining the overall GC responsiveness of ASM cells.

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supporting

confidence: 56%

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Bouazza

Debba-Pavard²,

Amrani³

et al. 2014

Am J Respir Cell Mol Biol

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“…The blood sampling was performed within 12 h of injury, making these results representative for the inflammatory phase before any infection of the injuries was likely to have occurred. The up‐regulation of GR expression is coherent with earlier experimental results showing an increased GR expression in splenic T lymphocytes from burn‐injured mice, although this increase was observed 10 days after injury. The observed increased GR expression may be a direct effect of the immediate inflammatory response following burn injury.…”

Section: Discussionsupporting

confidence: 90%

Glucocorticoid receptor expression and binding capacity in patients with burn injury

Bergquist

Huss

Hästbacka

et al. 2015

Acta Anaesthesiol Scand

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“…This suggests that a subset of GR-insensitive T lymphocytes could have been recruited into brain tissue following WNV infection and raises the possibility that brain inflammation in response to WNV may be destructive because the infiltrating leukocytes that cause the tissue damage lack the molecular machinery to respond to endogenous glucocorticoids that dampen inflammation. These results are similar to a previous report showing down-regulation of GR, MR, and ERα gene expression in microglia following inflammatory challenge in the brain (Sierra et al, 2008) but differ from a study showing an increase in GR expression and decrease in glucocorticoid sensitivity in splenic T cells of mice following thermal injury (D'Elia et al, 2010). Indeed, we also found that mice exposed to the lethal toxin of Clostridium sordellii exhibited lymphoid depletion in splenic tissue and apoptosis in thymic tissue, which is consistent with patterns of glucocorticoid-induced immune cell apoptosis.…”

Section: Discussionsupporting

confidence: 86%

Tissue expression of steroid hormone receptors is associated with differential immune responsiveness

Butts

Jones

Lim

et al. 2011

Brain, Behavior, and Immunity

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Glucocorticoids and other steroid hormones have been used as treatments against a number of diseases, especially inflammatory conditions in which the immune system is overactive. These treatments have varying degrees of responsiveness among individuals and in different tissues (including brain); therefore, it is important to determine what could account for these differences. In this study, we evaluated expression of steroid hormone receptors in immune cells from lymphoid and non-lymphoid tissues as a possible explanation for tissue-specific differences. We analyzed leukocytes (CD45 + ) in kidney, liver, spleen, and thymus tissues from healthy mice for expression of the receptor for stress hormone (glucocorticoid -GR) as well as other steroid hormones (androgen -AR, progesterone -PR) and found that all tissues expressed these steroid hormone receptors but with varying expression patterns. To determine whether tissue-specific differences were related to immune cell composition, we examined steroid hormone receptor expression in T lymphocytes from each of these tissues and found similar patterns of expression in these cells regardless of tissue source. Because glucocorticoids can also impact brain function, we further examined expression of the stress hormone receptor in brain tissue and found GR expressed in immune cells at this site. In order to investigate the potential impact in an area of neuropathology, we utilized a mouse model of West Nile Virus (WNV). We observed pathological changes in brains of WNV-infected animals and T lymphocytes in the areas of inflammation; however, these cells did not express GR. These data indicate that tissue-specific differences in steroid hormone receptor expression by immune cells could determine responsiveness with steroid hormone treatment.

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T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids

Abstract: . T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids.

Cited by 9 publications

References 49 publications

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Glucocorticoid receptor expression and binding capacity in patients with burn injury

Tissue expression of steroid hormone receptors is associated with differential immune responsiveness

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