Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle.
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-1beta 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 microM) and p38 (SB202190, 10 microM) 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.
Peng
Qi
Q
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, United Kingdom.
Matsuda
Takeshi
T
Hirst
Stuart J
SJ
D000328:Adult; D000368:Aged; D001249:Asthma / Q000276:immunology* / Q000517:prevention & control; D016535:Bronchial Hyperreactivity / Q000276:immunology; D002070:Butadienes / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018925:Chemokines / Q000276:immunology*; D019742:Chemokines, CC / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology; D007249:Inflammation; D018793:Interleukin-13 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D009130:Muscle, Smooth / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009570:Nitriles / Q000276:immunology / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000276:immunology; D011725:Pyridines / Q000276:immunology / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D007093:Imidazoles; D018793:Interleukin-13; D009570:Nitriles; D020319:Oligodeoxyribonucleotides, Antisense; D011725:Pyridines; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; C113580:U 0126; D015847:Interleukin-4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole