title: Neutrophil activation and survival are modulated by interaction with NK cells.
abstract: It is increasingly evident that neutrophils are able to cross-talk with other leukocytes to shape ongoing inflammatory and immune responses. In this study, we analyzed whether human NK cells may influence the survival and activation of neutrophils under co-culture conditions. We report that NK cells exposed to either IL-15 or IL-18 alone strongly protect the survival of neutrophils via the release of IFNγ and granulocyte macrophage colony-stimulating factor (GM-CSF) plus IFNγ, respectively, and cause a slight up-regulation of neutrophil CD64 and CD11b expression. In comparison, NK cells exposed to both IL-15 and IL-18 show a lesser ability to increase the survival of neutrophils but can more potently up-regulate CD64 and CD11b expression, as well as induce the de novo surface expression of CD69, in neutrophils. Analysis of the events occurring in neutrophil/NK co-cultures exposed to IL-15 plus IL-18 revealed that (i) neutrophil survival is positively affected by NK-derived GM-CSF but negatively influenced by a CD18-dependent neutrophil/NK contact, (ii) NK-derived IFNγ is almost entirely responsible for the induction of CD64, (iii) both soluble factors (primarily GM-CSF) and direct cell-cell contact up-regulate CD11b and CD69 and (iv) NK-derived GM-CSF induces the expression of biologically active heparin-binding EGF-like growth factor (HB-EGF) in neutrophils. Finally, we demonstrate that NK cells can also express HB-EGF when stimulated with either IL-2 or IL-15, yet independently of endogenous GM-CSF. Altogether, our results define a novel interaction within the innate immune system whereby NK cells, by directly modulating neutrophil functions, might contribute to the pathogenesis of inflammatory diseases.
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, Strada Le Grazie 8, Verona 37134, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Costantini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Micheletti
authors.forename: Federica
authors.initials: F
authors.lastname: Calzetti
authors.forename: Omar
authors.initials: O
authors.lastname: Perbellini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pizzolo
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
mesh_terms: D017209:Apoptosis; D002450:Cell Communication / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D016207:Cytokines; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins