title: IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK.
abstract: Human airway smooth muscle (HASM) cells express interleukin (IL)-13 and IL-4 receptors and respond to these cytokines with signal transducer and activator of transcription-6 and extracellular signal-regulated kinase (ERK) activation. The purpose of this study was to determine whether IL-13 and/or IL-4 influence eotaxin release in HASM cells and whether the ERK mitogen-activated protein (MAP) kinase pathway is involved in these events. Eotaxin release into HASM cell supernatants was assayed by ELISA, and eotaxin mRNA expression was determined by Northern blot analysis. Pretreatment with either IL-13 or IL-4 resulted in a concentration- and time-dependent release of eotaxin, although IL-4 was more effective. Eotaxin release was approximately twice baseline after treatment with 50 ng/ml IL-13 or IL-4 (P < 0.001). IL-13 and IL-4 also acted synergistically with tumor necrosis factor (TNF)-alpha to induce eotaxin release: TNF-alpha alone (10 ng/ml for 24 h) resulted in an approximately fourfold increase in eotaxin release, whereas TNF-alpha in combination with IL-13 or IL-4 resulted in 10- or 20-fold increases (P < 0.05). Similar results were obtained for eotaxin mRNA expression. Pretreatment with either U-0126 (10 microM) or PD-98059 (30 microM), both inhibitors of MAP/ERK kinase, the enzyme upstream of ERK, inhibited IL-13- or IL-4-induced eotaxin release (P < 0.05). U-0126 also inhibited IL-13, and TNF-alpha induced mRNA expression. Our results indicate that IL-13 and IL-4 cause eotaxin release in HASM cells through a mechanism that, in part, involves ERK activation and suggest that the smooth muscle may be an important source of chemokines leading to eosinophil recruitment in asthma.
authors.affiliation: Physiology Program, Harvard School of Public Health, 665 Huntington Ave., Bldg. 1 Rm. 311, Boston, MA 02115, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Moore
authors.forename: Trudi L
authors.initials: TL
authors.lastname: Church
authors.forename: David D
authors.initials: DD
authors.lastname: Chism
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Shore
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D014132:Trachea / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018793:Interleukin-13; D009570:Nitriles; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D015847:Interleukin-4; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one