TNF-α/IL-17 synergy inhibits IL-13 bioactivity via IL-13Rα2 induction

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TNF-α/IL-17 synergy inhibits IL-13 bioactivity via IL-13Rα2 induction Vahe Badalyan, MD, MPH, Robert Thompson, BSc, Kezia Addo, BSc, Lee A. Borthwick, PhD, Andrew J. Fisher, MD, PhD, Tatiana Ort, PhD, Timothy G. Myers, PhD, Thomas A. Wynn, PhD, Thirumalai R. Ramalingam, MBBS, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 4, Pages 975-978.e5 (October 2014) DOI: 10.1016/j.jaci.2014.05.019 Copyright © 2014 Terms and Conditions

Fig 1 TNF-α and IL-17 synergistically induce IL-13Rα2. Primary NLFs (A and B) were incubated with specified cytokines for 72 hours. Kinetics of IL13RA2 expression in NLFs, assayed at 24, 48, or 72 hours poststimulation (C) and decay postcytokine withdrawal (D). Flow cytometric measurement of IL-13Rα1 and IL-13Rα2 on ALF surface after cytokine stimulation (E and F). Expression of Il13ra1 and Il13ra2 transcripts in mouse lungs after TNF-α and IL-17 administration (G). ALF, Adult lung fibroblast; APC, Allophycocyanin; PE, phycoerythrin. Journal of Allergy and Clinical Immunology 2014 134, 975-978.e5DOI: (10.1016/j.jaci.2014.05.019) Copyright © 2014 Terms and Conditions

Fig 2 NLFs were treated with TNF-α and IL-17 for 72 hours, washed, and then treated with IL-13 in increasing concentrations (0.1-2.5 ng/mL) for 24 hours. Increased IL13RA2 induction is associated with loss of IL-13–induced CCL26 production (A and B). Recovery of IL-13– induced CCL26 expression by blocking IL-13Rα2 with mAb (C). Pairwise analyses of transcriptome signature of NLFs treated with IL-13 ± TNF/IL-17 pretreatment (PreTx), ±anti–IL-13Rα2 mAb (D). Also refer to Fig E3. Journal of Allergy and Clinical Immunology 2014 134, 975-978.e5DOI: (10.1016/j.jaci.2014.05.019) Copyright © 2014 Terms and Conditions

Fig E1 TNF-α and IL-17 synergistically induce IL-13Rα2 in human adult lung fibroblasts (ALFs). A, Primary lung fibroblasts from a healthy adult donor were treated with indicated cytokines for 72 hours. Transcript abundance of IL13RA2 was measured by using quantitative PCR. B, Primary ALFs from 5 healthy donors were cultured with indicated cytokines for 72 hours. Transcript abundance of IL13RA1 and IL13RA2 was quantified by using quantitative PCR. Box-and-whisker plots depict 25th-75th percentile range with median drawn inside, and error bars depict Tukey's interquartile range. Ratio paired t test used for calculating statistical significance between relevant treatment groups. *P < .05; **P < .01. Journal of Allergy and Clinical Immunology 2014 134, 975-978.e5DOI: (10.1016/j.jaci.2014.05.019) Copyright © 2014 Terms and Conditions

Fig E2 Induction of IL-13Rα2 by TNF-α and IL-17 in ALFs is associated with diminution of CCL26 expression by IL-13. Representative ALFs from a healthy donor were cultured with or without TNF-α and IL-17 for 72 hours. Media were replaced without or with low (0.5 ng/mL) or high (5 ng/mL) concentrations of IL-13 for 24 hours, at which time cells were harvested for RNA and quantitative PCR was performed for IL13RA2 and CCL26. ALFs, Adult lung fibroblasts. Journal of Allergy and Clinical Immunology 2014 134, 975-978.e5DOI: (10.1016/j.jaci.2014.05.019) Copyright © 2014 Terms and Conditions

Fig E3 Expression profile of differentially expressed transcripts in response to IL-13, ± IL-13Rα2 induction, ± anti–IL-13Rα2 mAb. A, List of experimental groups and their treatment conditions that were studied in quadruplicates by microarray. B, Heat-map of log2 expression level, relative to media-only control. After pretreatment to induce IL-13Rα2, IL-13 was added in the presence or absence of anti–IL-13Rα2-blocking mAb. Entries for IL13 with q value > 0.05 (comparing media control) are not color coded. C, Venn diagram of statistically significant expression changes, showing the number of probes having log2 fold change > 0.5 (up or down) and false discovery rate–adjusted P value < .05. Ab, Antibody. Journal of Allergy and Clinical Immunology 2014 134, 975-978.e5DOI: (10.1016/j.jaci.2014.05.019) Copyright © 2014 Terms and Conditions