title: Human eosinophil activin A synthesis and mRNA stabilization are induced by the combination of IL-3 plus TNF.
abstract: Eosinophils contribute to immune regulation and wound healing/fibrosis in various diseases, including asthma. Growing appreciation for the role of activin A in such processes led us to hypothesize that eosinophils are a source of this transforming growth factor-ß superfamily member. Tumor necrosis factor-α (TNF) induces activin A by other cell types and is often present at the site of allergic inflammation along with the eosinophil-activating common ß (ßc) chain-signaling cytokines (interleukin (IL)-5, IL-3, granulocyte-macrophages colony-stimulating factor (GM-CSF)). Previously, we established that the combination of TNF plus a ßc chain-signaling cytokine synergistically induces eosinophil synthesis of the remodeling enzyme matrix metalloproteinase-9. Therefore, eosinophils were stimulated ex vivo by these cytokines and in vivo through an allergen-induced airway inflammatory response. In contrast to IL-5+TNF or GM-CSF+TNF, the combination of IL-3+TNF synergistically induced activin A synthesis and release by human blood eosinophils. IL-3+TNF enhanced activin A mRNA stability, which required sustained signaling of pathways downstream of p38 and extracellular signal-regulated kinase mitogen-activated protein kinases. In vivo, following segmental airway allergen challenge of subjects with mild allergic asthma, activin A mRNA was upregulated in airway eosinophils compared with circulating eosinophils, and ex vivo, circulating eosinophils tended to release more activin A in response to IL-3+TNF. These data provide evidence that eosinophils release activin A and that this function is enhanced when eosinophils are present in an allergen-induced inflammatory environment. Moreover, these data provide the first evidence for posttranscriptional control of activin A mRNA. We propose that an environment rich in IL-3+TNF will lead to eosinophil-derived activin A, which has an important role in regulating inflammation and/or fibrosis.
authors.affiliation: Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Elizabeth A
authors.identifier: 0000-0001-7335-6698
authors.initials: EA
authors.lastname: Kelly
authors.affiliation: Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Esnault
authors.affiliation: Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Sean H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Lin Ying
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Mandy E
authors.initials: ME
authors.lastname: Burnham
authors.affiliation: Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Jarjour
mesh_terms: D028341:Activins / Q000378:metabolism*; D000328:Adult; D004789:Enzyme Activation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology*; D015848:Interleukin-5 / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D007377:Interleukin-3; D015848:Interleukin-5; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C422405:activin A; C103008:inhibin beta A subunit; D028341:Activins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D028322:Inhibin-beta Subunits; D020928:Mitogen-Activated Protein Kinases