title: 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.affiliation: Département de Sciences Cliniques, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
authors.forename: Anouk
authors.initials: A
authors.lastname: Lavoie-Lamoureux
authors.forename: Kantuta
authors.initials: K
authors.lastname: Moran
authors.forename: Guy
authors.initials: G
authors.lastname: Beauchamp
authors.forename: Susanne
authors.initials: S
authors.lastname: Mauel
authors.forename: Falko
authors.initials: F
authors.lastname: Steinbach
authors.forename: Josiane
authors.initials: J
authors.lastname: Lefebvre-Lavoie
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lavoie
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D020869:Gene Expression Profiling; D006736:Horses; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D018375:Neutrophil Activation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases