Back to Search
Start Over
IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
- Source :
- Gastroenterology, United States
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Background & Aims Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. Methods We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf–/–, Lta–/–, and Ltb–/– mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. Results Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp–/– mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte–derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. Conclusions Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.
- Subjects :
- WT, wild type
Male
0301 basic medicine
Colorectal cancer
Immune Regulation
Mice
chemistry.chemical_compound
Full Report: Basic and Translational—Alimentary Tract
AOM, azoxymethane
DC, dendritic cell
0302 clinical medicine
IEL, intraepithelial lymphocytes
DSS, dextran sodium sulfate
TNF-α, tumor necrosis factor alpha
Lymphotoxin-alpha
Original Research
IBD, inflammatory bowel disease
Gastroenterology
Interleukin
ILC, innate lymphoid cell
mRNA, messenger RNA
3. Good health
Survival Rate
CRC, colorectal cancer
shRNA, short hairpin RNA
Immunohistochemistry
Female
030211 gastroenterology & hepatology
Tumor necrosis factor alpha
cytokine signaling
NF-κB, nuclear factor κB
Colorectal Neoplasms
Tumor Suppressor
tumor suppressor
PBS, phosphate-buffered saline
03 medical and health sciences
medicine
Animals
Humans
RNA, Messenger
Aged
Inflammation
Cytokine Signaling
LTBR, lymphotoxin beta receptor
Hepatology
Azoxymethane
business.industry
BP, binding protein
immune regulation
Cancer
Receptors, Interleukin
medicine.disease
IL, interleukin
Disease Models, Animal
030104 developmental biology
Lymphotoxin
LT, lymphotoxin
chemistry
inflammation
Cancer research
Lymphotoxin beta receptor
business
MDDC, monocyte-derived dendritic cell
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 159
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....11d2062e4714eac52081850e5c3ec8fb