IL-4 activates equine neutrophils and induces a mixed inflammatory cytokine expression profile with enhanced neutrophil chemotactic mediator release ex vivo.
Abstract: Neutrophils are potent contributors to the lung pathophysiological changes occurring in allergic airway inflammation, which typically involve T helper type 2 (Th2) cytokine overexpression. We have previously reported that equine pulmonary endothelial cells are activated by the Th2 cytokine IL-4 and express chemotactic factors for neutrophils after stimulation. We have further explored the possible mechanisms linking Th2-driven inflammation and neutrophilia by studying the effects of recombinant equine IL-4, a prototypical Th2 cytokine, on peripheral blood neutrophils (PBN) isolated from normal animals and from horses with asthmatic airway inflammation (equine heaves). We found that IL-4 induced morphological changes in PBN, dose- and time-dependent expression of IL-8 mRNA, as well as the release of chemotactic factors for neutrophils in culture supernatants. Also, IL-4 induced a mixed inflammatory response in PBN from control and asthmatic-animals with increased expression of proinflammatory IL-8 and TNF-α but a marked inhibition of IL-1β. IL-4 type I receptor (IL-4Rα) and CD23 (FcεRII) expression were also upregulated by IL-4. Importantly, disease as well as chronic antigenic exposure modified gene expression by PBN. Finally, we found that activation of equine neutrophils with IL-4 involved STAT6 phosphorylation and p38 MAPK and phosphatidylinositol 3-kinase (PI3K); the pharmacological inhibitors, SB-203580 and LY-294002, respectively, significantly reversed IL-4-induced gene modulation in PBN. Overall, results from this study add to the link between Th2-driven inflammation and neutrophilia in the equine model and further extend the characterization of IL-4 effects on neutrophils.
Publication Date: 2010-07-16 PubMed ID: 20639353DOI: 10.1152/ajplung.00135.2009Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research examines how a typical T helper type 2 (Th2) cytokine, Interleukin-4 (IL-4), impacts neutrophils, a type of white blood cell, in horses with both healthy and asthmatic immune systems. The study finds that IL-4 prompts a mixed inflammatory response, influencing chemotactic factors and gene expression, suggesting a relationship between Th2-driven inflammation and an increase in neutrophils in horses.
Objective and Background
- This research aims to understand the relationship between Th2-driven inflammation and neutrophilia, i.e., an increase in neutrophils, by exploring the effects of IL-4 on peripheral blood neutrophils (PBN). This study builds on previous research which found that IL-4 activates equine pulmonary endothelial cells and causes them to express factors that attract neutrophils.
- Neutrophils contribute significantly to lung pathophysiological changes observed in allergic airway inflammation, which typically involves an overexpression of Th2 cytokines. Among these cytokines, IL-4 plays a central role.
Methods
- The researchers isolated PBN from healthy horses and from horses with asthmatic airway inflammation (equine heaves). They then exposed these cells to recombinant equine IL-4 and studied the response.
- To discern the intracellular signaling mechanisms, the researchers used pharmacological inhibitors (SB-203580 and LY-294002), which helped identify the involvement of STAT6 phosphorylation and two kinase proteins, p38 MAPK and PI3K, in the IL-4-induced responses.
Findings
- The study found that IL-4 introduces morphological changes in PBN and induces a dose- and time-dependent expression of IL-8 mRNA. This led to the release of chemotactic factors for neutrophils in culture supernatants.
- IL-4 triggers a mixed inflammatory response in PBN from both control and asthmatic animals, increasing the expression of pro-inflammatory IL-8 and TNF-α, but significantly inhibiting IL-1β.
- The researchers also observed an upregulation of IL-4 type I receptor (IL-4Rα) and CD23 (FcεRII) expression in response to IL-4.
- Additionally, the study showed that disease conditions and chronic antigenic exposure modified the gene expression in PBN. This suggests an influence of the health status and environmental conditions on the immune response of the animals.
- The IL-4 induced gene modulation in PBN was significantly reversed by the application of pharmacological inhibitors, indicating the involvement of STAT6 phosphorylation and the p38 MAPK and PI3K kinase proteins.
Conclusion
- This research provides further evidence of a link between Th2-driven inflammation and neutrophilia in horses and extends our understanding of IL-4’s effects on neutrophils. This could potentially influence future studies and treatments relating to equine health and immune response, especially in allergic and asthmatic conditions.
Cite This Article
APA
Lavoie-Lamoureux A, Moran K, Beauchamp G, Mauel S, Steinbach F, Lefebvre-Lavoie J, Martin JG, Lavoie JP.
(2010).
IL-4 activates equine neutrophils and induces a mixed inflammatory cytokine expression profile with enhanced neutrophil chemotactic mediator release ex vivo.
Am J Physiol Lung Cell Mol Physiol, 299(4), L472-L482.
https://doi.org/10.1152/ajplung.00135.2009 Publication
Researcher Affiliations
- Département de Sciences Cliniques, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
MeSH Terms
- Animals
- Asthma / genetics
- Asthma / metabolism
- Asthma / pathology
- Blotting, Western
- Chemotaxis, Leukocyte / immunology
- Gene Expression Profiling
- Horses
- Immunoenzyme Techniques
- Inflammation / genetics
- Inflammation / immunology
- Interleukin-4 / genetics
- Interleukin-4 / metabolism
- Interleukin-8 / genetics
- Interleukin-8 / metabolism
- Neutrophil Activation
- Phosphatidylinositol 3-Kinases / genetics
- Phosphatidylinositol 3-Kinases / metabolism
- RNA, Messenger / genetics
- Reverse Transcriptase Polymerase Chain Reaction
- STAT6 Transcription Factor / genetics
- STAT6 Transcription Factor / metabolism
- Tumor Necrosis Factor-alpha / genetics
- Tumor Necrosis Factor-alpha / metabolism
- p38 Mitogen-Activated Protein Kinases / genetics
- p38 Mitogen-Activated Protein Kinases / metabolism
Citations
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- Gu L, Liu H, Liu X, Zeng X, Lei Z, Wan X. The Relationship Between Interleukin-4 Levels and Cardiovascular Events in Patients with Chronic Kidney Disease. Risk Manag Healthc Policy 2020;13:2371-2377.
- Lee EA, Johnson LR, Johnson EG, Vernau W. Clinical features and radiographic findings in cats with eosinophilic, neutrophilic, and mixed airway inflammation (2011-2018). J Vet Intern Med 2020 May;34(3):1291-1299.
- Minden-Birkenmaier BA, Meadows MB, Cherukuri K, Smeltzer MP, Smith RA, Radic MZ, Bowlin GL. Manuka honey modulates the release profile of a dHL-60 neutrophil model under anti-inflammatory stimulation. J Tissue Viability 2020 May;29(2):91-99.
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