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- Title
Human eosinophil activin A synthesis and mRNA stabilization are induced by the combination of IL-3 plus TNF.
- Authors
Kelly, Elizabeth A; Esnault, Stephane; Johnson, Sean H; Liu, Lin Ying; Malter, James S; Burnham, Mandy E; Jarjour, Nizar N
- 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.
- Publication
Immunology & Cell Biology, 2016, Vol 94, Issue 7, p701
- ISSN
0818-9641
- Publication type
Article
- DOI
10.1038/icb.2016.30