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  • Original Paper
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IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes

Oncogene volume 19, pages 1596–1604 (2000)Cite this article

Abstract

The stress-activated pathways leading to activation of p38 MAP kinase (p38 MAPK) and c-jun N-terminal kinases (JNK) have been shown to be activated by pro-inflammatory cytokines, physical and chemical stresses as well as a variety of hematopoietic growth factors. One exception is interleukin (IL)-4, which does not activate this pathway in hematopoietic cell. We report here that in A431, a keratinocytic cell line, IL-4 activates Rac and Cdc42 and their downstream effector p21-activated kinase (PAK). Rac and Cdc42 appear to regulate a protein kinase cascade initiated at the level of PAK and leading to activation of p38 MAPK, since IL-4 stimulates tyrosine phosphorylation of p38 MAPK and increases its catalytic activity. As A431 cells are able to produce IL-6 in response to IL-4 stimulation, we assessed the involvement of p38 MAPK in IL-6 gene expression. A pyrimidazole compound, SB203580, a specific inhibitor of p38 MAPK, inhibits production and gene expression of IL-6. SB203580 reduced significantly the stability of IL-6 mRNA. Here we provide evidence that p38 MAPK is activated in response to IL-4 and is involved in IL-6 synthesis by stabilizing IL-6 mRNA.

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Abbreviations

AMV:

avian myeloblastosis virus

AP-1:

activator protein

ARE:

AU rich element

ATF-2:

activating transcription factor

C/EBP:

CCAAT/enhancer binding protein

CRIB:

Cdc42/Rac interacting binding

EGF:

epidermal growth factor

EMSA:

electrophoretic mobility shift assay

ERK:

extracellular regulated kinase

IL:

interleukin

IL-4R:

IL-4 receptor

IRS:

insulin receptor substrate

JAK:

janus kinase

JNK:

C-jun N terminal kinase

LPS:

lipopolysaccharide

MAP:

mitogen activated protein

NF-κB:

nuclear factor

PAGE:

polyacrylamide gel electrophoresis

PAK:

p21 activated kinase

Rb:

retinoblastoma

RBP-Jκ:

recombination signal-sequence binding protein

RT–PCR:

reverse transcriptase polynucleotide chain reaction

SAPK:

stress activated protein kinase

SH2:

src-homology 2

STAT:

signal transducer and activator of transcription

TNF:

transforming necrosis factor

UTR:

untranslated region

WASP:

Wiscott Aldrich Syndrome protein

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Acknowledgements

We are grateful to Dr N Vita for providing IL-4. Thanks are also extended to F Gouilleux, G Haegeman, J Imbert and H Jacquemin-Sablon for helpful discussion. This work was supported by fellowship to S Wery-Zennaro and grants from Association pour la Recherche sur le Cancer (Grants no 3014) and from Ligue Nationale Contre le Cancer (Comite des Hauts-de-Seine). JL Zugaza received an INSERM fellowship contributed by the Conseil Régional d'lle-de-France.

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  1. INSERM U461, Faculté de Pharmacie, 5, rue J B Clément, 92296 Chätenay-Malabry, Cedex, France

    Sandrine Wery-Zennaro, Jose L Zugaza, Martine Letourneur, Jacques Bertoglio & Josiane Pierre

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Wery-Zennaro, S., Zugaza, J., Letourneur, M. et al. IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes. Oncogene 19, 1596–1604 (2000). https://doi.org/10.1038/sj.onc.1203458

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