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IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis

Abstract

Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-β1 in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Rα2. Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-α. Second, it involves IL-13 signaling through IL-13Rα2 to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13Rα2 expression reduced production of TGF-β1 in oxazolone-induced colitis and that prevention of IL-13Rα2 expression, Il13ra2 gene silencing or blockade of IL-13Rα2 signaling led to marked downregulation of TGF-β1 production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Rα2 signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-β1–mediated fibrosis.

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Figure 1: Cytokines involved in the activation of the TGFB1 promoter and expression of IL-13Rα2.
Figure 2: IL-13 plus TNF-α–induced STAT6 and NF-κB are necessary for activation of the TGFB1 promoter.
Figure 3: MM6 cells that do not express IL-13Rα2 cannot support activation of the TGFB1 promoter.
Figure 4: AP-1 is necessary for activation of TGFB1 promoter.
Figure 5: Role of IL-13Rα2 expression in oxazolone-induced colitis and bleomycin-induced lung fibrosis.
Figure 6: Role of IL-13Rα2 signaling in bleomycin-induced lung fibrosis.

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Acknowledgements

This research was supported by the Intramural Research Program of the US National Institute of Allergy and Infectious Disease, National Institutes of Health. We thank I. Fuss and T. Watanabe for advice and help.

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Correspondence to Warren Strober.

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Supplementary information

Supplementary Fig. 1

Il13ra1 mRNA is constitutively expressed nd Il13ra2 mRNA is expressed in J774 cells after stimulation with IL-13 plus TNF-α or IL-4 plus TNF-α. (PDF 24 kb)

Supplementary Fig. 2

Inhibition of NK-κB by Bay 11-7082 prevents TGFB1 promoter activity in THP-1 cells. (PDF 27 kb)

Supplementary Fig. 3

IL-13Rα1 is constitutively expressed and IL-13Rα2 is expressed on approximately 25% of primary human monocytes after stimulation with IL-13 plus TNF-α or IL-4 plus TNF-α. (PDF 51 kb)

Supplementary Fig. 4

Induction of TGFB1 promoter activity downstream of IL-13Rα2 is NF-κB independent. (PDF 27 kb)

Supplementary Fig. 5

Induction of TGFB1 promoter activity downstream of IL-13Rα2 is PI3-K independent. (PDF 34 kb)

Supplementary Fig. 6

IL-13Rα1-specific antibody of MM6 cells causes downregulation of IL-13–induced STAT6 phosphorylation. (PDF 24 kb)

Supplementary Fig. 7

Il13rα2-specific siRNA inhibition IL-13Rα2 expression in J774 cells. (PDF 19 kb)

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Fichtner-Feigl, S., Strober, W., Kawakami, K. et al. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat Med 12, 99–106 (2006). https://doi.org/10.1038/nm1332

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