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Signaling Pathways Regulating Interleukin-13–stimulated Chemokine Release from Airway Smooth Muscle

Department of 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

Correspondence and requests for reprints should be addressed to Stuart J. Hirst, Ph.D., Department of Asthma, Allergy, and Respiratory Science, Guy's, King's and St Thomas' School of Medicine, Thomas Guy House, Guy's Hospital Campus, London SE1 9RT, UK. E-mail: stuart.hirst{at}kcl.ac.uk

Interleukin (IL)-13 receptor activation on airway smooth muscle cells induces eotaxin release and activates multiple signaling pathways including mitogen-activated protein 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 (ODNs) to downregulate endogenous STAT6 protein. STAT6 antisense ODNs were taken up by about 85% of cells. Selective downregulation of STAT6 protein occurred with antisense ODNs, but not with sense or scrambled ODNs. Eotaxin release induced by IL-13 or IL-4 (10 ng/ml) was reduced by 81 ± 4 and 75 ± 7%, respectively, in cells transfected with antisense ODNs (p < 0.001), but not with a sense ODN or a scrambled ODN. Eotaxin release induced by IL-1ß was unaffected by STAT6 antisense 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) mitogen-activated protein kinase pathways were combined in STAT6 antisense ODN-transfected cells. In contrast, about 25% of the response remained when each inhibitor was examined alone in STAT6 antisense ODN-treated cells. These data support roles for both STAT6- and mitogen-activated protein kinase–dependent pathways in mediating eotaxin release from airway smooth muscle by IL-13 or IL-4.

Key Words: airway smooth muscle • antisense oligodeoxynucleotide • eotaxin • mitogen-activated protein kinases • STAT6

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