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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 755-761

Interleukin-13 Upregulates Eotaxin Expression in Airway Epithelial Cells by a STAT6-Dependent Mechanism

Satoshi Matsukura,* Cristiana Stellato, Steve N. Georas, Vincenzo Casolaro, James R. Plitt, Katsushi Miura, Shin Kurosawa, Ulrike Schindler, and Robert P. Schleimer

Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland; and Tularik, Inc., South San Francisco, California

Interleukin (IL)-13 is a T helper 2-derived cytokine that has recently been implicated in allergic airway responses. We hypothesized that IL-13 may regulate expression of eotaxin in airway epithelium. We found that IL-13 upregulated eotaxin messenger RNA and protein synthesis in the airway epithelial cell line BEAS-2B; this effect showed synergy with tumor necrosis factor (TNF)-alpha and also was inhibited by the glucocorticoid budesonide. To establish the mechanisms of eotaxin upregulation by IL-13, cells were transfected with an eotaxin promoter-luciferase reporter plasmid and transcription was activated by IL-13 (1.7-fold) and TNF-alpha (2.8-fold). The combination of IL-13 and TNF-alpha additively activated the promoter constructs (4.1-fold). Activation of signal transducer and activator of transcription (STAT) 6 by IL-13 was confirmed by nuclear protein binding to a DNA probe derived from the eotaxin promoter. Activation of eotaxin transcription by IL-13 and the additive effect with TNF-alpha were lost in plasmids mutated at a putative STAT6 binding site. Cotransfection with a wild-type STAT6 expression vector significantly enhanced activation of the eotaxin promoter after IL-13 stimulation (6-fold induction). A significant increase of eotaxin protein secretion in the supernatant of STAT6 wild-type-transfected cells was observed after IL-13 stimulation. Cotransfection with a dominant negative STAT6 mutant expression vector inhibited activation of the eotaxin promoter by IL-13. These results indicate that IL-13 stimulates eotaxin expression in airway epithelial cells and that STAT6 plays a pivotal role in this response.

* Current address: First Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-0064, Japan. E-mail: smatsuku{at}post.cc.showa-u.ac.jp
Abbreviations: antibody, Ab; base pairs, bp; budesonide, BUD; dimethyl sulfoxide, DMSO; dithiothreitol, DTT; ethylenediaminetetraacetic acid, EDTA; enzyme-linked immunosorbent assay, ELISA; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; interleukin, IL; messenger RNA, mRNA; nuclear factor, NF; Nonidet P-40, NP-40; eotaxin promoter- luciferase reporter plasmid, pEotx; phenylmethylsulfonyl fluoride, PMSF; standard error of the mean, SEM; signal transducer and activator of transcription, STAT; the wild-type STAT6 expression vector, STAT6 WT; the tyrosine 641 mutant of STAT6, which acts as a dominant negative, STAT6 Y641; T helper, Th; tumor necrosis factor, TNF.




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