IL-3 maintains activation of the p90S6K/RPS6 pathway and increases translation in human eosinophils

Stephane Esnault, Elizabeth A B Kelly, Zhong Jian Shen, Mats W. Johansson, James S. Malter, Nizar N. Jarjour

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

IL-5 is a major therapeutic target to reduce eosinophilia. However, all of the eosinophil-activating cytokines, such as IL-5, IL-3, and GM-CSF, are typically present in atopic diseases, including allergic asthma. As a result of the functional redundancy of these three cytokines on eosinophils and the loss of IL-5R on airway eosinophils, it is important to take IL-3 and GM-CSF into account to efficiently reduce tissue eosinophil functions. Moreover, these three cytokines signal through a common b-chain receptor but yet differentially affect protein production in eosinophils. Notably, the increased ability of IL-3 to induce the production of proteins, such as semaphorin-7A, without affecting mRNA levels suggests a unique influence of IL-3 on translation. The purpose of this study was to identify the mechanisms by which IL-3 distinctively affects eosinophil function compared with IL-5 and GM-CSF, with a focus on protein translation. Peripheral blood eosinophils were used to study intracellular signaling and protein translation in cells activated with IL-3, GM-CSF, or IL-5. We establish that, unlike GM-CSF or IL-5, IL-3 triggers prolonged signaling through activation of ribosomal protein S6 (RPS6) and the upstream kinase 90-kDa ribosomal S6 kinase (p90S6K). Blockade of p90S6K activation inhibited phosphorylation of RPS6 and IL-3-enhanced semaphorin-7A translation. Furthermore, in an allergen-challenged environment, in vivo phosphorylation of RPS6 and p90S6K was enhanced in human airway compared with circulating eosinophils. Our findings provide new insights into the mechanisms underlying differential activation of eosinophils by IL-3, GM-CSF, and IL-5. These observations identify IL-3 and its downstream intracellular signals as novel targets that should be considered to modulate eosinophil functions.

Original languageEnglish (US)
Pages (from-to)2529-2539
Number of pages11
JournalJournal of Immunology
Volume195
Issue number6
DOIs
StatePublished - Sep 15 2015

Fingerprint

Ribosomal Protein S6
Interleukin-3
Eosinophils
Interleukin-5
Granulocyte-Macrophage Colony-Stimulating Factor
Semaphorins
Protein Biosynthesis
Cytokines
90-kDa Ribosomal Protein S6 Kinases
Intracellular Signaling Peptides and Proteins
Phosphorylation
Ribosomal Protein S6 Kinases
Eosinophilia
Allergens
Proteins
Asthma

ASJC Scopus subject areas

  • Immunology

Cite this

IL-3 maintains activation of the p90S6K/RPS6 pathway and increases translation in human eosinophils. / Esnault, Stephane; Kelly, Elizabeth A B; Shen, Zhong Jian; Johansson, Mats W.; Malter, James S.; Jarjour, Nizar N.

In: Journal of Immunology, Vol. 195, No. 6, 15.09.2015, p. 2529-2539.

Research output: Contribution to journalArticle

Esnault, Stephane ; Kelly, Elizabeth A B ; Shen, Zhong Jian ; Johansson, Mats W. ; Malter, James S. ; Jarjour, Nizar N. / IL-3 maintains activation of the p90S6K/RPS6 pathway and increases translation in human eosinophils. In: Journal of Immunology. 2015 ; Vol. 195, No. 6. pp. 2529-2539.
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