J Immunol 2012,
PMID: 22573806
Zhou, Xiuxia; Hu, Haizhen; Balzar, Silvana; Trudeau, John B; Wenzel, Sally E
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.
Diseases/Pathways annotated by Medline MESH: Asthma, Inflammation
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Text Mining Data
CCL11/eotaxin-1 ⊣ IL-4/IL-13: "
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
"
CCL11/eotaxin-1 ⊣ IL-4/IL-13: "
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
"
CCL11/eotaxin-1 → MAPK: "
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
"
IL-4/IL-13 — MAPK: "
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
"
IL-4/IL-13 — MAPK: "
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
"
CCL11 → IL-13: "
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 → IL-13: "
TGF-ß1 plus IL-13 synergistically increased STAT-6 phosphorylation, nuclear translocation, and binding to the CCL11 promoter as compared with IL-13 alone
"
IL-13 ⊣ IL-4Ra: "
Regulation of the IL-4Ra complex by TGF-ß1 augmented IL-13 signaling by dampening IL-13Ra2 expression, overcoming IL-13 's autoregulation of its pathway and enhancing the expression of CCL11
"
Manually curated Databases
No curated data.