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; Pérez, Laura García; Karstens, Karl-Frederick; Wöstemeier, Anna; Nawrocki, Mikołaj; Pelczar, Penelope; Witkowski, Mario; Nilsson, Sven Erik G.; 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; Pérez, Daniel Rodríguez; Strowig, Till; Koni, Pandelakis A.; Kruglov, Andrey; Sauter, Guido; Izbicki, Jakob R.; Guse, Andreas H.; Rösch, Thomas; Lohse, Ansgar W.; Flavell, Richard A.; Gagliani, Nicola; Huber, Samuel

doi:10.1053/j.gastro.2020.06.033

Cited by 32 publications

(38 citation statements)

References 58 publications

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“…Data presented in this study confirm the production of IL-22BP by MNP and eosinophils in CD gut tissues, but do not support a production by T cells in LP nor in MLN as recently reported by Huber's group 32,39 . The reason for the discrepancies regarding expression of IL22RA2 in human remain to be elucidated.…”

Section: Discussioncontrasting

confidence: 86%

“…We previously used tissue immunofluorescence to demonstrate that LP eosinophils were by far the most abundant IL-22BP expressing cells in normal and CD mucosa with few DCs expressing IL-22BP and none of IL-22BP-expressing cells expressing CD3 31 . Huber group used intracellular flow cytometry to demonstrate IL-22BP expression by DCs, eosinophils and CD4 + T cells from LP 32,39 , the levels of which were reported to be enhanced during IBD only in CD4 + T cells 32 .…”

Section: Discussionmentioning

confidence: 99%

“…We confirmed the high expression of IL22RA2 in human gut MNP and identified eosinophils as another source of IL-22BP in the LP of healthy and IBD tissues 31 , as later confirmed by Pelczar et al 32 . Interestingly, the latter further revealed unsuspected expression of IL-22BP by CD4 + T cells in human and mouse gut tissues 32,39 and suggested T cells also contributed to increased IL-22BP levels observed in the inflamed IBD intestine. This is of particular importance in IBD given the major pathophysiological implications linked to the increased production of IL-22BP observed in inflamed tissues 31,32 .…”

Section: Introductionmentioning

confidence: 95%

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IL-22BP production is heterogeneously distributed in Crohn’s disease

Fantou

Delbos²,

Abidi³

et al. 2021

Preprint

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Background & aims: IL-22 binding protein (IL-22BP) is a soluble and specific inhibitor of IL-22, a cytokine with known protective actions on intestinal epithelial cells during inflammation. Although eosinophils and mononuclear phagocytes (MNP) were shown to be the producers of IL-22BP in the intestine lamina propria (LP), it has recently been proposed that CD4+ T cells represent an additional source of IL-22BP in the gut during Crohn's disease (CD). In this study we sought to confirm these findings and to assess IL-22BP secretion levels. Methods: We investigated IL-22BP cellular sources in CD gut samples using qPCR and ELISA on FACS-sorted LP and mesenteric lymph nodes (MLN) cell subsets. We also evaluated IL-22BP levels in ex-vivo culture of intestinal biopsies. Results: MNP (HLA DR+ CD11c+ cells) and eosinophils isolated from LP CD tissues expressed IL22RA2, while the expression measured in the CD4+ and CD8+ T cells fractions was undetectable or 100-1000 times lower than in MNP. In MLN, IL22RA2 expression in T cells was either undetectable of 1000-fold lower than in MNPs without differences between naive and non-naive subsets. IL22RA2 expression was undetectable after ex vivo activation of both CD4+ and CD8+ T cells from LP or MLNs and IL-22BP was not detected in their supernatant, either activated or not. LP eosinophils appeared capable of secreting IL-22BP but not DCs likely due to in vitro activation as confirmed with monocyte-derived DCs. We also identified higher production of IL-22BP from ileum as compared to colon biopsies and demonstrated that IL-22BP levels correlated with those of eotaxins but not with TNF and IL-6. Finally, high ex vivo production of IL-22BP in mucosa biopsies from CD patients was only observed in smokers. Conclusion: We confirmed that eosinophils and MNPs are the major sources of IL-22BP in the gut during CD and found no clear evidence for IL-22BP expression by T cells. This work also provides new insights on factors regulating intestinal IL-22BP levels.

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Section: Discussioncontrasting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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IL-22BP production is heterogeneously distributed in Crohn’s disease

Fantou

Delbos²,

Abidi³

et al. 2021

Preprint

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“…At the same time, LTβR is amplified or overexpressed in HNSCCs of the larynx or oral cavity [ 48 ] and increased LTβR expression is associated with a worse overall survival in patients with non-small-cell lung cancer [ 47 ]. Nevertheless, LTβR signaling can suppress colorectal cancer development via the induction of IL-22bp, the level of which is downregulated in tumor tissues from patients with CRC and correlates with a poor prognosis [ 31 ].…”

Section: Tnf and Lt As Prognostic Markers And Their Polymorphismsmentioning

confidence: 99%

Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice

Gubernatorova

Polinova

Petropavlovskiy

et al. 2021

Cancers

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Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) are two related cytokines from the TNF superfamily, yet they mediate their functions in soluble and membrane-bound forms via overlapping, as well as distinct, molecular pathways. Their genes are encoded within the major histocompatibility complex class III cluster in close proximity to each other. TNF is involved in host defense, maintenance of lymphoid tissues, regulation of cell death and survival, and antiviral and antibacterial responses. LTα, known for some time as TNFβ, has pleiotropic functions including control of lymphoid tissue development and homeostasis cross talk between lymphocytes and their environment, as well as lymphoid tissue neogenesis with formation of lymphoid follicles outside the lymph nodes. Along with their homeostatic functions, deregulation of these two cytokines may be associated with initiation and progression of chronic inflammation, autoimmunity, and tumorigenesis. In this review, we summarize the current state of knowledge concerning TNF/LTα functions in tumor promotion and suppression, with the focus on the recently uncovered significance of host–microbiota interplay in cancer development that may explain some earlier controversial results.

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“…Once bound to IL-22, IL-22BP can successfully block and neutralize the activity of IL-22 in vitro [26][27][28] and in vivo [5] by decreasing its availability for IL-22RA1. IL-22BP has been reported to be produced by different cell types, among them are dendritic cells (DC) [5,29], eosinophils [29,30], and cluster of differentiation (CD)4 + T cells [29,31]. Generally, an inverse relation between IL-22BP and IL-22 can be observed in many tissues [5,21,32].…”

Section: Il-22 and Il-22bpmentioning

confidence: 99%

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

et al. 2021

Self Cite

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The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient’s immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by TH22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4+ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.

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

Cited by 32 publications

References 58 publications

IL-22BP production is heterogeneously distributed in Crohn’s disease

IL-22BP production is heterogeneously distributed in Crohn’s disease

Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

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