title: Balance between IL-3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils.
abstract: In contrast to eosinophils and neutrophils, the regulation of the lifespan of human basophils is poorly defined, with the exception of the potent anti-apoptotic effect of IL-3 that also promotes pro-inflammatory effector functions and phenotypic changes. Type I IFNs (IFN-α, IFN-β), which are well known for their anti-viral activities, have the capacity to inhibit allergic inflammation.
  
  
  
  To elucidate whether type I IFNs have the potential to abrogate the lifespan and/or effector functions of human basophils.
  
  
  
  We cultured human basophils, and for comparison, eosinophils and neutrophils, with IL-3, interferons, FasL and TRAIL, alone or in combination, and studied cell survival, effector functions and signalling pathways involved.
  
  
  
  Despite an identical pattern of early signalling in basophils, eosinophils and neutrophils in response to different types of interferons, only basophils displayed enhanced apoptosis after type I IFN treatment. IFN-γ prolonged survival of eosinophils but did not affect the lifespan of basophils. IFN-α-mediated apoptosis required STAT1-STAT2 heterodimers and the contribution of constitutive p38 MAPK activity. Whereas the death ligands FasL and TRAIL-induced apoptosis in basophils per se, IFN-α-mediated apoptosis did neither involve autocrine TRAIL signalling nor did it sensitize basophils to FasL-induced apoptosis. However, IFN-α and FasL displayed an additive effect in killing basophils. Interestingly, IL-3, which protected basophils from IFN-α-, TRAIL- or FasL-mediated apoptosis, did not completely block the additive effect of combined IFN-α and FasL treatment. Moreover, we demonstrate that IFN-α suppressed IL-3-induced release of IL-8 and IL-13. In contrast to IFN-α-mediated apoptosis, these inhibitory effects of IFN-α were not dependent on p38 MAPK signalling.
  
  
  
  Our study defines the unique and granulocyte-type-specific inhibitory and pro-apoptotic function of type I IFNs and their cooperation with death ligands in human blood basophils, which may be relevant for the anti-allergic properties of type I IFNs.
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|University Institute of Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: B R
authors.initials: BR
authors.lastname: Hagmann
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|University Institute of Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Odermatt
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Kaufmann
authors.affiliation: University Institute of Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: C A
authors.initials: CA
authors.lastname: Dahinden
authors.affiliation: University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|University Institute of Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: M
authors.identifier: 0000-0001-8208-3222
authors.initials: M
authors.lastname: Fux
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001491:Basophils / Q000276:immunology* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D053222:Fas Ligand Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D018793:Interleukin-13 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007370:Interferon Type I; D018793:Interleukin-13; D050791:STAT Transcription Factors; D053221:TNF-Related Apoptosis-Inducing Ligand; D007371:Interferon-gamma; D053612:Janus Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 
  TRAIL
  ; FasL; IL-3; JAK/STAT pathway; apoptosis; basophils; cytokine and chemokine production; eosinophils; neutrophils; p38 MAPK pathway; survival; type I IFN; type II IFN; type III IFN