MAPK regulation of IL-4/IL-13 receptors contributes to the synergistic increase in CCL11/eotaxin-1 in response to TGF-ß1 and IL-13 in human airway fibroblasts.
J Immunol
; 188(12): 6046-54, 2012 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-22573806
ABSTRACT
CCL11/eotaxin-1 is a potent eosinophilic CC chemokine expressed by primary human fibroblasts. The combination of TGF-ß1 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-ß1 plus IL-13. Transcriptional (nuclear run-on) and posttranscriptional (mRNA stability) assays confirmed that transcriptional regulation is critical for synergistic expression of CCL11. TGF-ß1 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-ß1 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-ß1 induced activation of the MEK/ERK pathway reduces IL-13Rα2 expression induced by IL-13. Thus, TGF-ß1, 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Asma
/
Regulação da Expressão Gênica
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MAP Quinases Reguladas por Sinal Extracelular
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Fator de Crescimento Transformador beta1
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Fibroblastos
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Pulmão
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article