IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis

Jarod A Zepp; Junjie Zhao; Caini Liu; Katazyna Bulek; Ling Wu; Xing Chen; Yujun Hao; Zhenghe Wang; Xinxin Wang; Wenjun Ouyang; Matthew F Kalady; Julie Carman; Wen-Pin Yang; Jun Zhu; Clare Blackburn; Yina H Huang; Thomas A Hamilton; Bing Su; Xiaoxia Li

doi:10.4049/jimmunol.1601540

IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis

J Immunol. 2017 Dec 1;199(11):3849-3857. doi: 10.4049/jimmunol.1601540. Epub 2017 Oct 25.

Authors

Jarod A Zepp^{1

2}, Junjie Zhao^{1

2}, Caini Liu¹, Katazyna Bulek¹, Ling Wu^{1

3}, Xing Chen¹, Yujun Hao⁴, Zhenghe Wang⁴, Xinxin Wang^{5

6}, Wenjun Ouyang⁷, Matthew F Kalady⁸, Julie Carman⁹, Wen-Pin Yang⁹, Jun Zhu⁹, Clare Blackburn¹⁰, Yina H Huang^{5

6}, Thomas A Hamilton^{1

2}, Bing Su^{11

12}, Xiaoxia Li^{13

2

3}

Affiliations

¹ Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
² Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195.
³ Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
⁴ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
⁵ Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755.
⁶ Department of Pathology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755.
⁷ Department of Immunology, Genentech, San Francisco, CA 94080.
⁸ Department of Stem Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
⁹ Discovery Biology, Bristol Myers-Squibb, Princeton, NJ 08540.
¹⁰ Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
¹¹ Department of Immunobiology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200125, China; and lix@ccf.org bingsu@sjtu.edu.cn.
¹² Department of Immunobiology, The Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06510.
¹³ Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; lix@ccf.org bingsu@sjtu.edu.cn.

Abstract

This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling in mice attenuated tissue repair of dextran sulfate sodium (DSS)-induced damage in colon epithelium and markedly reduced tumor development in an azoxymethane/DSS model of colitis-associated cancer. A novel IL-17A target gene, PLET1 (a progenitor cell marker involved in wound healing), was highly induced in DSS-treated colon tissues and tumors in an IL-17RC-dependent manner. PLET1 expression was induced in LGR5⁺ colon epithelial cells after DSS treatment. LGR5⁺PLET1⁺ marks a highly proliferative cell population with enhanced expression of IL-17A target genes. PLET1 deficiency impaired tissue repair of DSS-induced damage in colon epithelium and reduced tumor formation in an azoxymethane/DSS model of colitis-associated cancer. Our results suggest that IL-17A-induced PLET1 expression contributes to tissue repair and colon tumorigenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azoxymethane
Carcinogenesis
Cells, Cultured
Clustered Regularly Interspaced Short Palindromic Repeats
Colitis / chemically induced
Colitis / immunology*
Colon / metabolism*
Colon / pathology
Colonic Neoplasms / chemically induced
Colonic Neoplasms / immunology*
Dextran Sulfate
Epithelial Cells / immunology*
Gene Expression Regulation, Neoplastic
Interleukin-17 / genetics
Interleukin-17 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Pregnancy Proteins / genetics
Pregnancy Proteins / metabolism*
Receptors, Interleukin / genetics
Wound Healing

Substances

Il17rc protein, mouse
Interleukin-17
Plet-1 protein, mouse
Pregnancy Proteins
Receptors, Interleukin
Dextran Sulfate
Azoxymethane

Abstract

Publication types

MeSH terms

Substances

Grants and funding