Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis

Bockerstett, Kevin A.; Petersen, Christine; Noto, Christine; Kuehm, Lindsey M.; Wong, Chun Fung; Ford, Ethan; Teague, Ryan M.; Mills, Jason C.; Goldenring, James R.; DiPaolo, Richard J.

doi:10.1016/j.jcmgh.2020.04.014

Cited by 21 publications

(23 citation statements)

References 62 publications

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“…In the CTLA4 insufficiency model, treatment with anti-IL4-antibody and knockout of IL4Rα did not prevent inflammation but severed its link with the initiation of tumorigenesis ( Miska et al, 2018 ), suggesting that therapies targeting type 2 inflammation may be useful in promoting anti-cancer immunity or cancer prevention as well. This idea could be further supported by other models of gastric injury which have found that ILC2s are key mediators of a metaplastic response or that administration of IL27, an inhibitor of type 2 and other types of immunity ( Yoshida and Hunter, 2015 ; Tait Wojno et al, 2019 ), protects against metaplasia ( Bockerstett et al, 2020 ; Meyer et al, 2020 ).…”

Section: Type 2 Inflammatory Pathways Unveiled In Studies Of Autoimmune Tumorigenesis May Provide New Targets To Improve Cancer Immune Thmentioning

confidence: 79%

“…This condition has been modeled in mice, which undergo epithelial transformation to gastric metaplasia ( Nguyen et al, 2013 ). This model has suggested a link between autoimmunity and tumorigenesis, where administration of IL27, which may inhibit all three types of immunity ( Yoshida and Hunter, 2015 ; Tait Wojno et al, 2019 ), blocked the formation of metaplasia ( Bockerstett et al, 2020 ). The idea that type 2 inflammation induces epithelial transformation has been confirmed in an animal model system mimicking human CTLA4 insufficiency.…”

Section: Ctla4 Insufficiency and Other Models Of Autoimmune Gastritis Provide Experimental Evidence Of Autoimmunity-driven Tumorigenesismentioning

confidence: 99%

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Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Chen

2021

Front. Cell Dev. Biol.

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Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.

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Section: Type 2 Inflammatory Pathways Unveiled In Studies Of Autoimmune Tumorigenesis May Provide New Targets To Improve Cancer Immune Thmentioning

confidence: 79%

Section: Ctla4 Insufficiency and Other Models Of Autoimmune Gastritis Provide Experimental Evidence Of Autoimmunity-driven Tumorigenesismentioning

confidence: 99%

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Chen

2021

Front. Cell Dev. Biol.

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“…4,[9][10][11][12] In contrast, disruption of cytokines that exert anti-inflammatory effects, such as IL10 or IL27, may increase cancer risk. [13][14][15] Recent studies by our group have uncovered the broad anti-inflammatory role of the steroid hormones glucocorticoids and androgens within the stomach. 16,17 Loss of these hormones leads to spontaneous activation of the innate immune response, driving SPEM development.…”

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confidence: 99%

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

Busada

Khadka

Peterson

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Aberrant gastric inflammation damages the stomach and induces gastric metaplasia (spasmolytic polypeptideexpressing metaplasia). Increased expression of the RNA binding protein tristetraprolin suppresses adrenalectomyinduced gastric inflammation and spasmolytic polypeptideexpressing metaplasia development. BACKGROUND & AIMS:Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a wellestablished sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNAbinding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS:We used a TTP-overexpressing model, the TTPDadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS:We found that TTPDadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from highdose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS:Our results show that TTP exerts broad antiinflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling:

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“…In a prospective study, women who developed AIG were found to have T cell and macrophage infiltration in their stomach biopsies as well as increased HLA-DR (MHC II) expression on epithelial cells (Burman et al, 1992). Mast cells and eosinophils have also been identified in the setting of AIG, but their contribution to disease and the significance of infiltration have not yet been determined (Park et al, 2013;Bockerstett et al, 2020).…”

Section: Autoimmune Gastritismentioning

confidence: 99%

Two Distinct Etiologies of Gastric Cancer: Infection and Autoimmunity

Hoft

Noto

DiPaolo

2021

Front. Cell Dev. Biol.

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Gastric cancer is a leading cause of mortality worldwide. The risk of developing gastric adenocarcinoma, which comprises >90% of gastric cancers, is multifactorial, but most associated with Helicobacter pylori infection. Autoimmune gastritis is a chronic autoinflammatory syndrome where self-reactive immune cells are activated by gastric epithelial cell autoantigens. This cause of gastritis is more so associated with the development of neuroendocrine tumors. However, in both autoimmune and infection-induced gastritis, high risk metaplastic lesions develop within the gastric mucosa. This warrants concern for carcinogenesis in both inflammatory settings. There are many similarities and differences in disease progression between these two etiologies of chronic gastritis. Both diseases have an increased risk of gastric adenocarcinoma development, but each have their own unique comorbidities. Autoimmune gastritis is a primary cause of pernicious anemia, whereas chronic infection typically causes gastrointestinal ulceration. Both immune responses are driven by T cells, primarily CD4+ T cells of the IFN-γ producing, Th1 phenotype. Neutrophilic infiltrates help clear H. pylori infection, but neutrophils are not necessarily recruited in the autoimmune setting. There have also been hypotheses that infection with H. pylori initiates autoimmune gastritis, but the literature is far from definitive with evidence of infection-independent autoimmune gastric disease. Gastric cancer incidence is increasing among young women in the United States, a population at higher risk of developing autoimmune disease, and H. pylori infection rates are falling. Therefore, a better understanding of these two chronic inflammatory diseases is needed to identify their roles in initiating gastric cancer.

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Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis

Cited by 21 publications

References 62 publications

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

Two Distinct Etiologies of Gastric Cancer: Infection and Autoimmunity

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