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.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Xiuxia ZhouSally E Wenzel

Abstract

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 inf...Continue Reading

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Citations

May 17, 2014·Bioanalysis·Stephanie Fraser, Catherine Soderstrom
Jun 14, 2014·Clinical and Experimental Medicine·Kihyuk ShinSeung-Hyo Lee
Mar 24, 2020·Journal of Leukocyte Biology·Michael YousefAdam J MacNeil
Jun 24, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Nicolas PionnierJoseph D Turner
Jun 30, 2019·The Journal of Experimental Medicine·Batika M J RanaAndrew N J McKenzie
Jan 7, 2015·British Journal of Pharmacology·G S MagalhãesM J Campagnole-Santos
Oct 2, 2019·Experimental and Therapeutic Medicine·Jie YangZhongfu Ma
Feb 8, 2020·Protein and Peptide Letters·Yang ZhaoZhongcheng Liu

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