Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFα in human epidermal keratinocytes (HaCaT)

Onda, Kenji; Nagashima, Masahiro; Kawakubo, Yo; Inoue, Shota; Hirano, Toshihiko; Oka, Kitaro

doi:10.1016/j.bbrc.2006.10.032

Cited by 27 publications

(23 citation statements)

References 29 publications

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“…We confirmed this in our cells. Activation of the MEK/ERK and p38 pathways has been shown to induce phosphorylation of the GR and decrease its translocation to the nucleus causing GC insensitivity in various cell types [13,24,25]. However, our data do not support a role for the MEK/ERK and p38 MAPK pathways in IL-17A-induced GC insensitivity in airway epithelial cells, since specific inhibition of these pathways could not block the IL-17A-induced effects.…”

Section: Discussioncontrasting

confidence: 55%

Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells

Zijlstra¹,

Hacken²,

Hoffmann³

et al. 2011

Eur Respir J

152

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A subset of asthma patients suffer from glucocorticoid (GC) insensitivity. T-helper cell type 17 cells have an emerging role in GC insensitivity, although the mechanisms are still poorly understood.We investigated whether interleukin (IL)-17A induces GC insensitivity in airway epithelium by studying its effects on responsiveness of tumour necrosis factor (TNF)-a-induced IL-8 production to budesonide in human bronchial epithelial 16HBE cells. We unravelled the underlying mechanism by the use of specific pathway inhibitors, reporter and overexpression constructs and a histone deacetylase (HDAC) activity assay.We demonstrated that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduced the sensitivity of TNF-a-induced IL-8 production to budesonide. IL-17A activated the p38, extracellular signal-related kinase (ERK) and phosphoinositide-3-kinase (PI3K) pathways, and the latter appeared to be involved in IL-17A-induced GC insensitivity. Furthermore, IL-17A reduced HDAC activity, and overexpression of HDAC2 reversed IL-17A-induced GC insensitivity. In contrast, IL-17A did not affect budesonide-induced transcriptional activity of the GC receptor, suggesting that IL-17A does not impair the actions of the ligated GC receptor.In conclusion, we have shown for the first time that IL-17A induces GC insensitivity in airway epithelium, which is probably mediated by PI3K activation and subsequent reduction of HDAC2 activity. Thus, blockade of IL-17A or downstream signalling molecule PI3K may offer new strategies for therapeutic intervention in GC-insensitive asthma.

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Section: Discussioncontrasting

confidence: 55%

Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells

Zijlstra¹,

Hacken²,

Hoffmann³

et al. 2011

Eur Respir J

152

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“…Activation of GR depends, as mentioned above, not only on ligand binding but also, on the phosphorylation state of the receptor which can accelerate its nuclear translocation or, its export. MEK inhibition restores the nuclear translocation of GR in some systems [58,59]; however, PD98059 treatment also promotes nuclear export of ERK/MAPK + Sgk into the cytoplasm [60]. As the transrepressive effect of glucocorticoids occurs only if glucocorticoids are present during the phase of active transcription [48], and we have shown that for mutual interference to occur, dex and 8Br-cAMP (or noradrenaline) must be added simultaneously (if dex is added 10 min before PKA stimulation, the interference is no longer observed) [61], the present results suggest that inhibition of ERK or p38 affects the nucleocytoplasmic traffic of activated GR, eliminating the interaction with pCREB (or PKA) leaving pCREB able to induce TRH transcription.…”

Section: Discussionmentioning

confidence: 99%

The PKC and ERK/MAPK Pathways Regulate Glucocorticoid Action on TRH Transcription

et al. 2008

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Biosynthesis of TRH, a neuropeptide involved in energy homeostasis, is modulated by glucocorticoids. TRH mRNA and peptide levels are increased upon incubation of hypothalamic cells with dexamethasone or with cAMP analogs but when combined, a mutual antagonism is observed. These effects are observed at the transcriptional level and on binding of glucocorticoid receptor (GR) or pCREB to the composite GRE (cGRE) and CRE-2 sites of TRH promoter. The present work studied the involvement of PKC and MAPK pathways on the effect of dexamethasone and on its interaction with cAMP signaling in hypothalamic cell cultures. PKC or MEK inhibition abolished dexamethasone-stimulatory effect on TRH mRNA levels, as well as its interference with the stimulatory effect of 8Br-cAMP. Binding of nuclear extracts from hypothalamic or neuroblastoma cells stimulated with dexamethasone or 8Br-cAMP to oligonucleotides containing the CRE or cGRE sites of TRH gene promoter was decreased if cells were preincubated with PKC or MEK inhibitors. Mutations on the AP-1 or the GRE half sites of cGRE showed that GR binds as an heterodimer on cGRE, and PKC or MEK inhibitors diminish binding at the AP-1 site. PKC and ERK signaling thus modulate GR activity and its interaction with CREB or AP-1 at the TRH gene promoter.

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“…It was shown that curcumin, which has antiinflammatory and antioxidant activities, protects the intestinal mucosal barrier by induction of MKP1 and subsequent inactivation of p38 and of NF-κB-mediated transcription (50). In addition, some reports suggest that ERK could be an important mediator of TNF-induced shock and provide a link with MKP1 (51,52). However, because we observed identical phospho-p38 and phospho-ERK levels in Mkp1 +/+ and Mkp1 -/-mice, the contribution of these MAPKs in the context of the present study can be ruled out.…”

Section: Figurementioning

confidence: 99%

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Vandevyver¹,

Dejager²,

Bogaert³

et al. 2012

J. Clin. Invest.

125

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Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation.Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1 -/-mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1 -/-mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1 -/-mice showed no change in sensitivity to TNF, Jnk2 -/-mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1 -/-and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.

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Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFα in human epidermal keratinocytes (HaCaT)

Cited by 27 publications

References 29 publications

Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells

Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells

The PKC and ERK/MAPK Pathways Regulate Glucocorticoid Action on TRH Transcription

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

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