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 TGF-β superfamily member. TNFα (TNF) induces activin A by other cell types and is often present at the site of allergic inflammation along with the eosinophil activating common β (βc) chain-signaling cytokines (IL-5, IL-3, GM-CSF). Previously, we established that the combination of TNF plus a βc chain-signaling cytokine synergistically induces eosinophil synthesis of the remodeling enzyme MMP-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 ERK MAP kinases. In vivo, following segmental airway allergen challenge of subjects with mild allergic asthma, activin A mRNA was upregulated in airway eosinophils compared to circulating eosinophils, and ex vivo, circulating eosinophils tended to release 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 post-transcriptional control of activin A mRNA. We propose that, an environment rich in IL-3+TNF will lead to eosinophil–derived activin A, which plays an important role in regulating inflammation and/or fibrosis.