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Published ahead of print on December 11, 2003, doi:10.1164/rccm.200307-888OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 5, March 2004, 596-603

A more recent version of this article appeared on March 1, 2004
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Submitted on July 8, 2003
Accepted on December 10, 2003

Signaling pathways regulate interlukin-13-stimulated chemokine release from airway smooth muscle

Qi Peng1, Takeshi Matsuda1, and Stuart J Hirst1*

1 Asthma, Allergy and Respiratory Science, Guy's, King's and St. Thomas' School of Medicine, King's College London, Guy's Hospital Campus, London, United Kingdom

* To whom correspondence should be addressed. E-mail: stuart.hirst{at}kcl.ac.uk.

IL-13 receptor activation on airway smooth muscle (ASM) cells induces eotaxin release and activates multiple signaling pathways including mitogen-activated protein (MAP) kinases, and signal transducer and activator of transcription 6 (STAT6). To examine a requirement for STAT6 in mediating IL-13-stimulated eotaxin release we used antisense oligodeoxynucleotides (AS-ODNs) to downregulate endogenous STAT6 protein. STAT6 AS-ODNs were taken up by ~ 85% of cells. Selective downregulation of STAT6 protein occurred with AS-ODNs, but not with sense or scrambled-ODNs. Eotaxin release induced by 10 ng/ml IL-13 or IL-4 was reduced by 81 ± 4 % and 75 ± 7 %, respectively in cells transfected with AS-ODN (p < 0.001), but not with sense or a scrambled-ODN. Eotaxin release induced by IL-1{beta} was unaffected by STAT6 AS-ODN (p > 0.05). Finally, IL-13- or IL-4-dependent eotaxin release was abolished when inhibitors of both p42/p44 ERK (U0126, 10 µM) and p38 (SB202190, 10 µM) MAP kinase pathways were combined in STAT6 AS-ODN transfected cells. In contrast, ~ 25% of the response remained when each inhibitor was examined alone in STAT6 AS-ODN treated cells. These data support roles for both STAT6- and MAP kinase-dependent pathways in mediating eotaxin release from ASM by IL-13 or IL-4.
Key words: Airway remodeling, airway smooth muscle, eotaxin, MAP kinase, STAT6, antisense oligodeoxynucleotide




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