Abstract
The intestinal epithelial barrier plays a critical role in the mucosal immunity. However, it remains largely unknown how the epithelial barrier is maintained after damage. Here we show that growth factor FGF2 synergized with interleukin-17 (IL-17) to induce genes for repairing of damaged epithelium. FGF2 or IL-17 deficiency resulted in impaired epithelial proliferation, increased pro-inflammatory microbiota outgrowth, and consequently worse pathology in a DSS-induced colitis model. The dysregulated microbiota in the model induced transforming growth factor beta 1 (TGFβ1) expression, which in turn induced FGF2 expression mainly in regulatory T cells. Act1, an essential adaptor in IL-17 signaling, suppressed FGF2-induced ERK activation through binding to adaptor molecule GRB2 to interfere with its association with guanine nucleotide exchange factor SOS1. Act1 preferentially bound to IL-17 receptor complex, releasing its suppressive effect on FGF2 signaling. Thus, microbiota-driven FGF2 and IL-17 cooperate to repair the damaged intestinal epithelium through Act1-mediated direct signaling cross-talk.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cells, Cultured
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Colitis / genetics
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Colitis / immunology
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Colitis / metabolism
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / immunology*
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Fibroblast Growth Factor 2 / metabolism
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Gene Expression Profiling / methods
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HEK293 Cells
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HT29 Cells
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HeLa Cells
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Humans
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-17 / metabolism
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Intestinal Mucosa / immunology
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Intestines / immunology*
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Intestines / microbiology
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Intestines / pathology
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microbiota / genetics
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Microbiota / immunology
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Oligonucleotide Array Sequence Analysis
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
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Wound Healing / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-17
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Traf3ip2 protein, mouse
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Transforming Growth Factor beta
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Fibroblast Growth Factor 2