scholarly journals Dexamethasone and RU24858 Induce Survival and Growth Factor Receptor Bound protein 2, Leukotriene B4 Receptor 1 and Annexin-1 expression in primary Human Neutrophils

2012 ◽  
Vol 5 ◽  
pp. JCD.S9097 ◽  
Author(s):  
Mirkka Janka-Junttila ◽  
Hannele Hasala ◽  
Ian Adcock ◽  
Eeva Moilanen ◽  
Hannu Kankaanranta
Keyword(s):  
Growth Factor Receptor ◽  
Leukotriene B4 ◽  
Human Neutrophils ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Gm Csf ◽  
Annexin 1 ◽  
Inducible Genes ◽  
Neutrophil Survival ◽  
Leukotriene B4 Receptor

Glucocorticoids are widely used anti-inflammatory medication in diseases like asthma and chronic obstructive pulmonary disease. Glucocorticoids can either activate (transactivation) or inhibit (transrepression) transcription. RU24858 was introduced as a “dissociated” glucocorticoid and it has been reported to transrepress but not to transactivate. The aim of this study was to compare the effects of RU24858 and dexamethasone in human neutrophils. RU24858 delayed spontaneous neutrophil apoptosis and further enhanced GM-CSF- induced neutrophil survival to a similar extent as dexamethasone. Like dexamethasone RU24858 also reduced CXCL8 and MIP-1α. Unexpectedly however, RU24858 increased the expression of the glucocorticoid-inducible genes BLT-1, Annexin-1 and Grb-2 in neutrophils to a similar level as seen with dexamethasone. We have shown here that dexamethasone and RU24858 both increase Grb-2, BLT1 and Annexin-1 expression and inhibit CXCL8 and MIP-1α production. This suggests that RU24858 was not able to dissociate between transactivation and transrepression in human neutrophils but enhanced neutrophil survival.

scholarly journals Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

2019 ◽  
Author(s):  
A. Rahman ◽  
K. M. Henry ◽  
K. D. Herman ◽  
A. A. R Thompson ◽  
H. M. Isles ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Human Neutrophils ◽  
Chronic Obstructive ◽  
Neutrophil Apoptosis ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Injury Model ◽  
Neutrophil Survival

AbstractNeutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafishin vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown ofegfraanderbb2by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

scholarly journals Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Atiqur Rahman ◽  
Katherine M Henry ◽  
Kimberly D Herman ◽  
Alfred AR Thompson ◽  
Hannah M Isles ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Human Neutrophils ◽  
Chronic Obstructive ◽  
Neutrophil Apoptosis ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Injury Model ◽  
Neutrophil Survival

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

Role of PI3-kinase–dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2607-2616 ◽  
Author(s):  
Andrew S. Cowburn ◽  
Karen A. Cadwallader ◽  
Benjamin J. Reed ◽  
Neda Farahi ◽  
Edwin R. Chilvers
Keyword(s):  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Pi3 Kinase ◽  
Human Neutrophils ◽  
Marginal Effect ◽  
Mrna Levels ◽  
Gm Csf ◽  
Tnf Α ◽  
Neutrophil Survival ◽  
Survival Effect

Phosphoinositide 3-kinase (PI3-kinase)–dependent phosphorylation of the proapoptotic Bcl-2 family member Bad has been proposed as an important regulator of apoptotic cell death. To understand the importance of this pathway in nontransformed hematopoietic cells, we have examined the effect of survival cytokines on PI3-kinase activity and Bad expression and phosphorylation status in human neutrophils. Granulocyte macrophage–colony-stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) both reduced the rate of apoptosis in neutrophils cultured in vitro for 20 hours. Coincubation with the PI3-kinase inhibitor LY294002, which in parallel experiments abolished GM-CSF–primed, fMLP-stimulated superoxide anion production and GM-CSF–stimulated PtdIns(3,4,5)P3accumulation, inhibited the GM-CSF and TNF-α survival effect. In contrast, the MAP kinase kinase (MEK1/2) inhibitor PD98059 and the protein kinase A inhibitor H-89 had only a marginal effect on GM-CSF–mediated neutrophil survival. GM-CSF substantially increased Bad phosphorylation at Ser112 and Ser136 and increased the cytosolic accumulation of Bad. GM-CSF also regulated Bad at a transcription level with a marked decrease in mRNA levels at 4 hours. TNF-α caused a biphasic effect on the rate of morphologic apoptosis, which corresponded to an early increase, and a late inhibition, of Bad mRNA levels. LY294002 inhibited GM-CSF– and TNF-α–mediated changes in Bad phosphorylation and mRNA levels. These data suggest that the survival effect of GM-CSF and TNF-α in neutrophils is caused by a PI3-kinase–dependent phosphorylation and cytosolic translocation of Bad, together with an inhibition of Bad mRNA levels. This has important implications for the regulation of neutrophil apoptosis in vivo.

scholarly journals Mcl-1 Expression in Human Neutrophils: Regulation by Cytokines and Correlation With Cell Survival

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2495-2502 ◽  
Author(s):  
Dale A. Moulding ◽  
Julie A. Quayle ◽  
C. Anthony Hart ◽  
Steven W. Edwards
Keyword(s):  
Acute Inflammation ◽  
Molecular Mechanisms ◽  
Human Neutrophils ◽  
Potential Mechanism ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Regulated Gene Expression ◽  
Neutrophil Survival ◽  
Stimulating Factor

Abstract Human neutrophils possess a very short half-life because they constitutively undergo apoptosis. Cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and other agents can rescue neutrophils from apoptosis but the molecular mechanisms involved in this rescue are undefined. Here, we show by Western blotting that human neutrophils do not express Bcl-2 or Bcl-X but constitutively express Bax. However, cellular levels of these proteins are unaffected by agents which either accelerate or delay neutrophil apoptosis. In contrast, neutrophils express the antiapoptotic protein Mcl-1 and levels of this protein correlate with neutrophil survival. Thus, cellular levels of Mcl-1 decline as neutrophils undergo apoptosis and are enhanced by agents (eg, GM-CSF, interleukin-1β, sodium butyrate, and lipopolysaccharide) that promote neutrophil survival. Neutrophils only possess few, small mitochondria, and much of the Mcl-1 protein seems to be located in nuclear fractions. These observations provide the first evidence implicating a Bcl-2 family member in the regulation of neutrophil survival. Moreover, this work also provides a potential mechanism whereby cytokine-regulated gene expression regulates the functional lifespan of neutrophils and hence their ability to function for extended time periods during acute inflammation.

scholarly journals Mycoplasma pneumoniae Modulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins

2014 ◽  
Vol 82 (12) ◽  
pp. 5246-5255 ◽  
Author(s):  
Yonghua Hao ◽  
Zhizhou Kuang ◽  
Jia Jing ◽  
Jinfeng Miao ◽  
Li Yu Mei ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Mycoplasma Pneumoniae ◽  
Growth Factor Receptor ◽  
Interleukin 4 ◽  
Chronic Obstructive ◽  
Signal Pathways ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Content Type ◽  
Mucus Hypersecretion

ABSTRACTAberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis.Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced byM. pneumoniaeremains unclear. This study aimed to determine the mechanism by whichM. pneumoniaeinduces mucus hypersecretion by usingM. pneumoniaeinfection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated thatM. pneumoniaeinduced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure toM. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated thatM. pneumoniaeinduces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.

scholarly journals Functional Properties and Molecular Architecture of Leukotriene A4 Hydrolase, a Pivotal Catalyst of Chemotactic Leukotriene Formation

2002 ◽  
Vol 2 ◽  
pp. 1734-1749 ◽  
Author(s):  
Jesper Z. Haeggström ◽  
Pär Nordlund ◽  
Marjolein M.G.M. Thunnissen
Keyword(s):  
Inflammatory Diseases ◽  
Biological Effects ◽  
Leukotriene B4 ◽  
Aminopeptidase Activity ◽  
Chronic Obstructive ◽  
Molecular Architecture ◽  
Obstructive Pulmonary Disease ◽  
Recent Developments ◽  
Leukotriene A4 Hydrolase ◽  
Leukotriene A4

The leukotrienes are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4is a classical chemoattractant, which triggers adherence and aggregation of leukocytes to the endothelium at only nM concentrations. In addition, leukotriene B4modulates immune responses, participates in the host defense against infections, and is a key mediator of PAF-induced lethal shock. Because of these powerful biological effects, leukotriene B4 is implicated in a variety of acute and chronic inflammatory diseases, e.g., nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease. The final step in the biosynthesis of leukotriene B4is catalyzed by leukotriene A4hydrolase, a unique bifunctional zinc metalloenzyme with an anion-dependent aminopeptidase activity. Here we describe the most recent developments regarding our understanding of the function and molecular architecture of leukotriene A4hydrolase.

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