Signaling pathways regulating interleukin-13–stimulated chemokine release from airway smooth muscle

Q Peng, T Matsuda, SJ Hirst - … journal of respiratory and critical care …, 2004 - atsjournals.org
Q Peng, T Matsuda, SJ Hirst
American journal of respiratory and critical care medicine, 2004atsjournals.org
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 …
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-1β 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.
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