Leukotriene B&lt;sub&gt;4&lt;/sub&gt; Receptors on Neutrophils in Patients with Psoriasis and Atopic Eczema

Meier, Friedegund; Groß, Eva; Klotz, Karl‐Norbert; Ruzicka, Thomas

doi:10.1159/000210802

Cited by 14 publications

(6 citation statements)

References 20 publications

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“…The normal affinity of the receptor in psoriasis argues against a genetic defect in protein structure. The defect in psoriasis seems to be specific for IZHETE binding, since our previous studies in psoriatic granulocytes showed normal binding of the arachidonic acid metabolite leukotriene Bq [26].…”

Section: Discussionmentioning

confidence: 83%

“…The defect in psoriasis seems to be specific for IZHETE binding, since our previous studies in psoriatic granulocytes showed normal binding of the arachidonic acid metabolite leukotriene Bq [26]. The reduced number of 12(S)-HETE receptors has a functional consequence in a parallel decrease of internalization of the ligand in psoriatic versus normal keratinocytes.…”

Section: Discussionmentioning

confidence: 84%

See 1 more Smart Citation

Defect of epidermal 12(S)‐hydroxyeicosatetraenoic acid receptors in psoriasis

Arenberger

Kemény

Ruzicka

1992

Eur J Clin Investigation

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12-hydroxyeicosatetraenoic acid (12-HETE) is assumed to play a central role in the pathophysiology of psoriasis. Since its effects in skin are mediated by specific high-affinity receptors, we studied the receptor characteristics in cultured epidermal cells from involved and apparently healthy skin of psoriasis patients by radioligand binding assay. Involved and uninvolved psoriatic epidermal cells showed a fourfold decrease in the number of 12-HETE binding sites as compared with normal healthy individuals and patients with atopic dermatitis, while receptor affinity remained unchanged. The decrease in receptor number was evident in psoriatic cells even in long-term culture and was not due to receptor down-regulation, defective response to interferon gamma or to protease degradation of receptor protein. The decrease in the number of 12-HETE receptors detectable even in clinically normal psoriatic skin functionally leads to diminished 12-HETE uptake and may thus represent a primary central molecular defect in the pathophysiology of the disease.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 84%

Defect of epidermal 12(S)‐hydroxyeicosatetraenoic acid receptors in psoriasis

Arenberger

Kemény

Ruzicka

1992

Eur J Clin Investigation

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“…Neutrophils have been implicated in the pathogenesis of many diseases, including severe asthma 12, psoriasis 34, and a variety of collagen-vascular diseases 56. These cells are known to be less sensitive to glucocorticoids than other white blood cell types 7.…”

Section: Introductionmentioning

confidence: 99%

High Constitutive Glucocorticoid Receptor β in Human Neutrophils Enables Them to Reduce Their Spontaneous Rate of Cell Death in Response to Corticosteroids

Strickland

Kisich

Hauk

et al. 2001

The Journal of Experimental Medicine

204

159

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Neutrophils are markedly less sensitive to glucocorticoids than T cells, making it difficult to control inflammation in neutrophil-mediated diseases. Development of new antiinflammatory strategies for such diseases would be aided by an understanding of mechanisms underlying differential steroid responsiveness. Two protein isoforms of the human glucocorticoid receptor (GR) exist, GRα and GRβ, which arise from alternative splicing of the GR pre-mRNA primary transcripts. GRβ does not bind glucocorticoids and is an inhibitor of GRα activity. Relative amounts of these two GRs can therefore determine the level of glucocorticoid sensitivity. In this study, human neutrophils and peripheral blood mononuclear cells (PBMCs) were studied to determine the relative amounts of each GR isoform.The mean fluorescence intensity (MFI) using immunofluorescence analysis for GRα was 475 ± 62 and 985 ± 107 for PBMCs and neutrophils, respectively. For GRβ, the MFI was 350 ± 60 and 1,389 ± 143 for PBMCs and neutrophils, respectively (P < 0.05). After interleukin (IL)-8 stimulation of neutrophils, there was a statistically significant increase in intensity of GRβ staining to 2,497 ± 140 (P < 0.05). No change in GRα expression was observed. This inversion of the GRα/GRβ ratio in human neutrophils compared with PBMCs was confirmed by quantitative Western analysis. Increased GRβ mRNA expression in neutrophils at baseline, and after IL-8 exposure, was observed using RNA dot blot analysis. Increased levels of GRα/GRβ heterodimers were found in neutrophils as compared with PBMCs using coimmunoprecipitation/Western analysis. Transfection of mouse neutrophils, which do not contain GRβ, resulted in a significant reduction in the rate of cell death when treated with dexamethasone.We conclude that high constitutive expression of GRβ by human neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death. Moreover, upregulation of this GR by proinflammatory cytokines such as IL-8 further enhances their survival in the presence of glucocorticoids during inflammation.

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“…Neutrophils have been implicated in the pathogenesis of many diseases including COPD, severe asthma, psoriasis, and a variety of collagen-vascular diseases [105,106]. These cells are less sensitive to glucocorticoids than other white blood cell types.…”

Section: Neutrophilic Inflammationmentioning

confidence: 99%

Mode of Glucocorticoid Actions in Airway Disease

Ito

Getting

Charron

2006

The Scientific World JOURNAL

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Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5%) of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD) do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR), which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

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Leukotriene B<sub>4</sub> Receptors on Neutrophils in Patients with Psoriasis and Atopic Eczema

Cited by 14 publications

References 20 publications

Defect of epidermal 12(S)‐hydroxyeicosatetraenoic acid receptors in psoriasis

Defect of epidermal 12(S)‐hydroxyeicosatetraenoic acid receptors in psoriasis

High Constitutive Glucocorticoid Receptor β in Human Neutrophils Enables Them to Reduce Their Spontaneous Rate of Cell Death in Response to Corticosteroids

Mode of Glucocorticoid Actions in Airway Disease

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