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.

• Authors: Anouk Lavoie-Lamoureux, Kantuta Moran, Guy Beauchamp, Susanne Mauel, Falko Steinbach, Josiane Lefebvre-Lavoie, James G Martin, Jean-Pierre Lavoie
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 299 Issue 4 Pg. L472-82 (Oct 2010) ISSN: 1522-1504 [Electronic] United States
• PMID: 20639353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-8
• RNA, Messenger
• STAT6 Transcription Factor
• STAT6 protein, human
• Tumor Necrosis Factor-alpha
• Interleukin-4
• Phosphatidylinositol 3-Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Asthma (genetics, metabolism, pathology)
• Blotting, Western
• Chemotaxis, Leukocyte (immunology)
• Gene Expression Profiling
• Horses
• Immunoenzyme Techniques
• Inflammation (genetics, immunology)
• Interleukin-4 (genetics, metabolism)
• Interleukin-8 (genetics, metabolism)
• Neutrophil Activation
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT6 Transcription Factor (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)