Role of intracellular kinases in the regulation of equine eosinophil migration and actin polymerization.
Abstract: Inappropriately activated eosinophils can contribute to disease pathogenesis and intracellular signalling pathways that regulate functional responses may represent a therapeutic target. Little is known about intracellular signalling in equine eosinophils and this study examined the role of phospholipase C (PLC) and a range of protein kinases on responses to histamine and CCL11. Histamine (10(-4) M) or CCL11 (5.6 x 10(-9) M)-induced actin polymerization, migration and superoxide production by eosinophils from healthy horses were compared in the presence and absence of selective kinase inhibitors. Inhibition of phosphatidylinositol-3 kinase (PI3K) significantly reduced the response in each assay. In contrast, whilst inhibition of PLC decreased actin polymerization and superoxide production, an increase in migration was observed; the latter effect was also seen when protein kinase C (PKC) was inhibited. With the exception of histamine-induced migration, which was significantly reduced by blocking extracellular regulated kinase (ERK)1/2, activation of ERK1/2, p38 MAPK and tyrosine kinase did not appear to play an important role in the responses studied. These results suggest that equine eosinophil activation by histamine and CCL11 is mediated through PI3K. Whilst PLC activation is required for actin polymerization and superoxide production, migration may be negatively regulated by PLC and PKC. These kinases represent potential targets for modulating eosinophil activation by multiple stimuli.
Publication Date: 2008-01-08 PubMed ID: 18177316DOI: 10.1111/j.1365-2885.2007.00922.xGoogle Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigates how certain intracellular kinases, more specifically phospholipase C (PLC) and phosphatidylinositol-3 kinase (PI3K), influence the behaviour of eosinophils in horses. The study reveals that the eosinophil response to histamine and CCL11 is largely controlled by PI3K, and suggests that these kinases might be potential targets for controlling eosinophil activation and treating related diseases.
Introduction and Motivation
- Eosinophils, when wrongly activated, can lead to diseases, and the signaling pathways that control these functional responses can be therapeutic targets.
- There is limited understanding of intracellular signaling in eosinophils specifically from equines (horses), prompting this study.
- The research aimed to examine the role of phospholipase C (PLC) and a variety of protein kinases in response to histamine and CCL11 – two substances that trigger an immune response.
Methodology and Results
- Histamine or CCL11-induced actions like actin polymerization, migration, and superoxide production by eosinophils were studied in both the presence and absence of selective kinase inhibitors.
- Blocking PI3K led to a significant decrease in each of the actions in the assays.
- Contrarily, while blocking PLC resulted in decreased actin polymerization and superoxide production, it caused an increase in migration; a similar effect was observed when protein kinase C (PKC) was inhibited.
- Except for histamine-induced migration, which was considerably reduced when extracellular regulated kinase (ERK) 1/2 was blocked, activation of ERK1/2, p38 MAPK, and tyrosine kinase did not seem to play a significant role in the studied responses.
Conclusion and Future Directions
- The study concludes that the activation of equine eosinophils by histamine and CCL11 is primarily mediated through PI3K.
- PLC activation seems to be necessary for actin polymerization and superoxide production, however, PLC and PKC may negatively regulate migration.
- The identified kinases, particularly PI3K, could be potential targets for controlling eosinophil activation.
Cite This Article
APA
Weston MC, Collins ME, Cunningham FM.
(2008).
Role of intracellular kinases in the regulation of equine eosinophil migration and actin polymerization.
J Vet Pharmacol Ther, 31(1), 31-38.
https://doi.org/10.1111/j.1365-2885.2007.00922.x Publication
Researcher Affiliations
- Department of Veterinary Basic Sciences and Pathology and Infectious Diseases, The Royal Veterinary College, Hertfordshire, UK. marie.weston@piramed.com
MeSH Terms
- Actins / drug effects
- Animals
- Cell Movement / drug effects
- Cells, Cultured
- Chemokine CCL11 / pharmacology
- Enzyme Inhibitors / pharmacology
- Eosinophils / cytology
- Eosinophils / drug effects
- Eosinophils / physiology
- Estrenes / pharmacology
- Histamine / pharmacology
- Horses / physiology
- Indoles / pharmacology
- Protein Kinase C / antagonists & inhibitors
- Pyrrolidinones / pharmacology
- Signal Transduction / physiology
- Type C Phospholipases / antagonists & inhibitors
- Type C Phospholipases / pharmacology
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