Cargando…

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Kempski, Jan, Giannou, Anastasios D., Riecken, Kristoffer, Zhao, Lilan, Steglich, Babett, Lücke, Jöran, Garcia-Perez, Laura, Karstens, Karl-Frederick, Wöstemeier, Anna, Nawrocki, Mikolaj, Pelczar, Penelope, Witkowski, Mario, Nilsson, Sven, Konczalla, Leonie, Shiri, Ahmad Mustafa, Kempska, Joanna, Wahib, Ramez, Brockmann, Leonie, Huber, Philipp, Gnirck, Ann-Christin, Turner, Jan-Eric, Zazara, Dimitra E., Arck, Petra C., Stein, Alexander, Simon, Ronald, Daubmann, Anne, Meiners, Jan, Perez, Daniel, Strowig, Till, Koni, Pandelakis, Kruglov, Andrey A., Sauter, Guido, Izbicki, Jakob R., Guse, Andreas H., Rösch, Thomas, Lohse, Ansgar W., Flavell, Richard A., Gagliani, Nicola, Huber, Samuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: W.B. Saunders 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607422/
https://www.ncbi.nlm.nih.gov/pubmed/32585307
http://dx.doi.org/10.1053/j.gastro.2020.06.033
_version_ 1783604645787074560
author Kempski, Jan
Giannou, Anastasios D.
Riecken, Kristoffer
Zhao, Lilan
Steglich, Babett
Lücke, Jöran
Garcia-Perez, Laura
Karstens, Karl-Frederick
Wöstemeier, Anna
Nawrocki, Mikolaj
Pelczar, Penelope
Witkowski, Mario
Nilsson, Sven
Konczalla, Leonie
Shiri, Ahmad Mustafa
Kempska, Joanna
Wahib, Ramez
Brockmann, Leonie
Huber, Philipp
Gnirck, Ann-Christin
Turner, Jan-Eric
Zazara, Dimitra E.
Arck, Petra C.
Stein, Alexander
Simon, Ronald
Daubmann, Anne
Meiners, Jan
Perez, Daniel
Strowig, Till
Koni, Pandelakis
Kruglov, Andrey A.
Sauter, Guido
Izbicki, Jakob R.
Guse, Andreas H.
Rösch, Thomas
Lohse, Ansgar W.
Flavell, Richard A.
Gagliani, Nicola
Huber, Samuel
author_facet Kempski, Jan
Giannou, Anastasios D.
Riecken, Kristoffer
Zhao, Lilan
Steglich, Babett
Lücke, Jöran
Garcia-Perez, Laura
Karstens, Karl-Frederick
Wöstemeier, Anna
Nawrocki, Mikolaj
Pelczar, Penelope
Witkowski, Mario
Nilsson, Sven
Konczalla, Leonie
Shiri, Ahmad Mustafa
Kempska, Joanna
Wahib, Ramez
Brockmann, Leonie
Huber, Philipp
Gnirck, Ann-Christin
Turner, Jan-Eric
Zazara, Dimitra E.
Arck, Petra C.
Stein, Alexander
Simon, Ronald
Daubmann, Anne
Meiners, Jan
Perez, Daniel
Strowig, Till
Koni, Pandelakis
Kruglov, Andrey A.
Sauter, Guido
Izbicki, Jakob R.
Guse, Andreas H.
Rösch, Thomas
Lohse, Ansgar W.
Flavell, Richard A.
Gagliani, Nicola
Huber, Samuel
author_sort Kempski, Jan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7607422
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher W.B. Saunders
record_format MEDLINE/PubMed
spelling pubmed-76074222020-11-06 IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans Kempski, Jan Giannou, Anastasios D. Riecken, Kristoffer Zhao, Lilan Steglich, Babett Lücke, Jöran Garcia-Perez, Laura Karstens, Karl-Frederick Wöstemeier, Anna Nawrocki, Mikolaj Pelczar, Penelope Witkowski, Mario Nilsson, Sven Konczalla, Leonie Shiri, Ahmad Mustafa Kempska, Joanna Wahib, Ramez Brockmann, Leonie Huber, Philipp Gnirck, Ann-Christin Turner, Jan-Eric Zazara, Dimitra E. Arck, Petra C. Stein, Alexander Simon, Ronald Daubmann, Anne Meiners, Jan Perez, Daniel Strowig, Till Koni, Pandelakis Kruglov, Andrey A. Sauter, Guido Izbicki, Jakob R. Guse, Andreas H. Rösch, Thomas Lohse, Ansgar W. Flavell, Richard A. Gagliani, Nicola Huber, Samuel Gastroenterology Original Research 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. W.B. Saunders 2020-10 /pmc/articles/PMC7607422/ /pubmed/32585307 http://dx.doi.org/10.1053/j.gastro.2020.06.033 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Kempski, Jan
Giannou, Anastasios D.
Riecken, Kristoffer
Zhao, Lilan
Steglich, Babett
Lücke, Jöran
Garcia-Perez, Laura
Karstens, Karl-Frederick
Wöstemeier, Anna
Nawrocki, Mikolaj
Pelczar, Penelope
Witkowski, Mario
Nilsson, Sven
Konczalla, Leonie
Shiri, Ahmad Mustafa
Kempska, Joanna
Wahib, Ramez
Brockmann, Leonie
Huber, Philipp
Gnirck, Ann-Christin
Turner, Jan-Eric
Zazara, Dimitra E.
Arck, Petra C.
Stein, Alexander
Simon, Ronald
Daubmann, Anne
Meiners, Jan
Perez, Daniel
Strowig, Till
Koni, Pandelakis
Kruglov, Andrey A.
Sauter, Guido
Izbicki, Jakob R.
Guse, Andreas H.
Rösch, Thomas
Lohse, Ansgar W.
Flavell, Richard A.
Gagliani, Nicola
Huber, Samuel
IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
title IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
title_full IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
title_fullStr IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
title_full_unstemmed IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
title_short IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans
title_sort il22bp mediates the antitumor effects of lymphotoxin against colorectal tumors in mice and humans
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607422/
https://www.ncbi.nlm.nih.gov/pubmed/32585307
http://dx.doi.org/10.1053/j.gastro.2020.06.033
work_keys_str_mv AT kempskijan il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT giannouanastasiosd il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT rieckenkristoffer il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT zhaolilan il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT steglichbabett il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT luckejoran il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT garciaperezlaura il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT karstenskarlfrederick il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT wostemeieranna il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT nawrockimikolaj il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT pelczarpenelope il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT witkowskimario il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT nilssonsven il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT konczallaleonie il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT shiriahmadmustafa il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT kempskajoanna il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT wahibramez il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT brockmannleonie il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT huberphilipp il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT gnirckannchristin il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT turnerjaneric il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT zazaradimitrae il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT arckpetrac il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT steinalexander il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT simonronald il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT daubmannanne il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT meinersjan il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT perezdaniel il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT strowigtill il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT konipandelakis il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT kruglovandreya il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT sauterguido il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT izbickijakobr il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT guseandreash il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT roschthomas il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT lohseansgarw il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT flavellricharda il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT gaglianinicola il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans
AT hubersamuel il22bpmediatestheantitumoreffectsoflymphotoxinagainstcolorectaltumorsinmiceandhumans