MAPK regulation of IL-4/IL-13 receptors contributes to the synergistic increase in CCL11/eotaxin-1 in response to TGF-β1 and IL-13 in human airway fibroblasts

CCL11/eotaxin-1 is a potent eosinophilic CC chemokine expressed by primary human fibroblasts. The combination of TGF-β1 and IL-13 synergistically increases CCL11 expression, but the mechanisms behind the synergy are unclear. To address this, human airway fibroblast cultures from normal and asthmatic...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2012-06, Vol.188 (12), p.6046-6054
Main Authors: Zhou, Xiuxia, Hu, Haizhen, Balzar, Silvana, Trudeau, John B, Wenzel, Sally E
Format: Article
Language:English
Subjects:
Asthma - immunology
Asthma - metabolism
Blotting, Western
Chemokine CCL11 - immunology
Chemokine CCL11 - metabolism
Chromatin Immunoprecipitation
Extracellular Signal-Regulated MAP Kinases - immunology
Extracellular Signal-Regulated MAP Kinases - metabolism
Fibroblasts - immunology
Fibroblasts - metabolism
Fluorescent Antibody Technique
Gene Expression Profiling
Gene Expression Regulation - immunology
Humans
Inflammation - immunology
Inflammation - metabolism
Interleukin-13 - immunology
Interleukin-13 - metabolism
Lung - immunology
Lung - metabolism
Receptors, Interleukin-13 - immunology
Receptors, Interleukin-13 - metabolism
Receptors, Interleukin-4 - immunology
Receptors, Interleukin-4 - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction - immunology
STAT6 Transcription Factor - immunology
STAT6 Transcription Factor - metabolism
Transforming Growth Factor beta1 - immunology
Transforming Growth Factor beta1 - metabolism
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Summary:CCL11/eotaxin-1 is a potent eosinophilic CC chemokine expressed by primary human fibroblasts. The combination of TGF-β1 and IL-13 synergistically increases CCL11 expression, but the mechanisms behind the synergy are unclear. To address this, human airway fibroblast cultures from normal and asthmatic subjects were exposed to IL-13 alone or TGF-β1 plus IL-13. Transcriptional (nuclear run-on) and posttranscriptional (mRNA stability) assays confirmed that transcriptional regulation is critical for synergistic expression of CCL11. TGF-β1 plus IL-13 synergistically increased STAT-6 phosphorylation, nuclear translocation, and binding to the CCL11 promoter as compared with IL-13 alone. STAT-6 small interfering RNA significantly knocked down both STAT-6 mRNA expression and phosphorylation and inhibited CCL11 mRNA and protein expression. Regulation of the IL-4Rα complex by TGF-β1 augmented IL-13 signaling by dampening IL-13Rα2 expression, overcoming IL-13's autoregulation of its pathway and enhancing the expression of CCL11. Our data suggest that TGF-β1 induced activation of the MEK/ERK pathway reduces IL-13Rα2 expression induced by IL-13. Thus, TGF-β1, a pleiotropic cytokine upregulated in asthmatic airways, can augment eosinophilic inflammation by interfering with IL-13's negative feedback autoregulatory loop under MEK/ERK-dependent conditions.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1102760