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Induction of the IL-13 receptor α2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways

Oncogene volume 20, pages 6660–6668 (2001)Cite this article

Abstract

IL-4 and IL-13 are related cytokines which induce both pro- and anti-inflammatory effects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Rα and γc and only binds IL-4, whereas, in the type II receptor, IL-4Rα dimerizes with IL-13Rα1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Rα2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Rα2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Rα2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Rα2 mRNA expression, but potentiated the effects of IL-4 or IL-13 on IL-13Rα2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Rα2 mRNA even in absence of stimulation. Our findings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13Rα2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process.

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Abbreviations

ERK:

Extracellular signal regulated kinase

IL:

Interleukin

IL-4R:

IL-4 receptor

JAK:

Janus Kinase

MAPK:

Mitogen activated protein kinase

PAGE:

Polyacrylamide gel electrophoresis

RT–PCR:

Reverse transcription-polymerase chain reaction

STAT:

Signal transducer and activator of transcription

MEK:

MAPK or ERK kinase

MKK:

MAP kinase kinase

HA:

Haemagglutinin

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Acknowledgements

We are grateful to Dr N Vita for providing IL-4 and IL-13. Thanks are also extended to F Gouilleux, A Brunet and J Raingeaud for providing us with the different plasmids used in this study. This work was supported by a fellowship to M David and grants from Association pour la Recherche sur le Cancer (Grants n°5963), and grants from the Samuel and Ester Chester Research Foundation.

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Authors and Affiliations

  1. INSERM U461, Faculte de Pharmacie, 5, rue JB Clement, Chatenay Malabry Cedex, 92296, France

    Muriel David, Jacques Bertoglio & Josiane Pierre

  2. Roger Williams Medical Center, Boston University School of Medicine, Providence, R102908, Rhode Island, USA

    Dwayne Ford & Abby L Maizel

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  1. Muriel David
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Correspondence to Josiane Pierre.

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David, M., Ford, D., Bertoglio, J. et al. Induction of the IL-13 receptor α2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways. Oncogene 20, 6660–6668 (2001). https://doi.org/10.1038/sj.onc.1204629

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