Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 115, Issue 3, Pages 514-520Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2004.11.033
Keywords
signal transducer and activator of transcription 3; extracellular signal-regulated kinase; c-Jun N-terminal kinase; IL-4R alpha; monocyte chemoattractant protein 1; vascular endothelial growth factor
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Funding
- NHLBI NIH HHS [HL68153, HL33009, HL67664, K08 HL004395, HL04395, P50 HL067664, P01 HL033009, R01 HL068153, P01 HL067664] Funding Source: Medline
- NIEHS NIH HHS [ES00002] Funding Source: Medline
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Background: Eotaxin is implicated in asthmatic eosinophilia. Oncostatin M (OSM) causes eotaxin release from fibroblasts. Objective: We sought to examine the effects and mechanism of action of OSM and other IL-6 family cytokines on eotaxin release from human airway smooth muscle cells. Methods: Eotaxin 1 release was measured by means of ELISA. Western blotting was used to examine mitogen-activated protein kinase and signal transducer and activator of transcription 3 (STAT-3) phosphorylation. Eotaxin promoter activity was analyzed in cells transfected with wild-type STAT-3, a mutant form of STAT-3 that cannot be phosphorylated, and a constitutively active form of STAT-3. The mRNA and protein expression of IL-4R alpha, the signaling receptor for IL-4 and IL-13, was evaluated by means of real-time PCR and flow cytometry, respectively. Results: OSM increased eotaxin I release and augmented IL-4-or IL-13-induced eotaxin release, whereas other IL-6 family cytokines did not. OSM caused a greater increase in STAT-3 phosphorylation and STAT-3-mediated gene transcription than other IL-6 family cytokines. OSM increased eotaxin promoter activity and augmented IL-13- and IL-4-induced increases in promoter activity. The constitutively active form of STAT-3 increased eotaxin promoter activity, whereas the mutant form of STAT-3 that cannot be phosphorylated significantly reduced eotaxin promoter activity induced by OSM or IL-4 plus OSM. OSM increased IL-4R alpha mRNA and protein levels. Conclusions: OSM induces eotaxin 1 expression in human airway smooth muscle cells by a mechanism involving STAT-3. OSM synergizes with IL-13 and 11-4 to increase eotaxin I expression, possibly as a result of effects on IL-4Ra expression.
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