The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response

Pagliari, Danilo; Cianci, Rossella; Frosali, Simona; Landolfi, Raffaele; Cammarota, Giovanni; Newton, Estelle E.; Pandolfi, Franco

doi:10.1016/j.cytogfr.2013.05.004

Cited by 57 publications

(60 citation statements)

References 108 publications

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“…17 Deregulation of the physiological environment around this layer may contribute to the development of autoimmune diseases such as celiac disease or IBD. 16,17,22 We have identified five new IL-15Ra isoforms, not previously known, that co-exist in the intestinal epithelial cells. Two of them were derived from variants 1 and 2; the remaining isoforms were derived from variant 3.…”

Section: Discussionmentioning

confidence: 99%

“…In autoimmune conditions, such as celiac disease and IBD, both IL-15 and IL-15Ra are up-regulated in the intestinal mucosa of patients suffering from these diseases, and this is maintained in patients with clinical remission. 16,30 As a result, the proportion of CD8 + T cells or intraepithelial lymphocytes is increased and a chronic inflammation of the mucosa is developed. In colorectal cancer, IL-15 can play a dual role as a protective factor with anti-tumor effects, 31 and a contributor to mucosal hyperplasia and angiogenesis, resulting in tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…15 Some pathologies where the IL-15/IL-15Ra system is deregulated include celiac disease, inflammatory bowel disease (IBD) or colorectal cancer. 16 The present work is focused on the intestinal epithelial cells as they are at the front line, with contact with dietary components and microbiota within the gut, and they are also capable of signaling to immune cells. 17 In addition, the regulation of IL-15Ra was studied, particularly on the description of the IL-15Ra splice variants as they specifically vary depending on the tissue.…”

Section: Introductionmentioning

confidence: 99%

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New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

et al. 2016

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IL-15 is a pleiotropic cytokine related to IL-2 which acts at a broader level than its counterpart. It is presented through its specific high-affinity receptor, IL-15Ra. Both cytokine and receptor are tightly regulated at multiple levels and are widely distributed. Thus, deregulation of their expression leads to an inflammatory immune response. Variants of splicing of IL-15Ra have been described in immune and barrier cells; however, their presence has not been focused on intestinal epithelial cells. In this study, we describe five new alternative variants of splicing of IL-15Ra in Caco-2 cells. Four of them were expressed into proteins inside Caco-2 cells, but these were unable to bind IL-15 or to follow the secretory pathway. However, the expression of mRNA itself might be relevant to diseases such as celiac disease, inflammatory bowel disease or colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

et al. 2016

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“…NKG2D can trigger antigen-specific lymphocyte-mediated cytotoxicity and direct cytolytic function in effector CD8 T cells, linking innate and adaptive immunity [44]. The peptide (α-gliadin 31-43) p31-43/49 activates the production of IL-15 and NK receptor-mediated IELs cytotoxicity [44,45] and also induces apoptosis of enterocytes, upregulates MHC class I molecules, activates MAP kinase pathway and upregulates the expression dendritic cells [46]. Another participant in the pathogenesis of CD is IL-15, of which both intestinal epithelia and dendritic cells/ macrophages are major sources in the intestine [41,47]; its role in the activation of innate and adaptive immunity in CD is currently well confirmed [41,46,48].…”

Section: Gluten Damage In the Small Intestinal Mucosamentioning

confidence: 99%

Celiac disease: understanding the gluten-free diet

2016

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“…42 These features indicate that IL-15 has a dominant effect on the pathogenesis of inflammation and is an important member of the mucosal 'immunological niche'. 43 Collectively, our data show that IL-15 directly controls B-1a cells by modulating their responses to proinflammatory signals. Understanding the pivotal role of IL-15 in B-1a cells will reveal how these cells are triggered to restrain the infections that are a consistent threat to the gut.…”

Section: Il-15 Augmented Igm and Iga Expressionmentioning

confidence: 89%

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

et al. 2015

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Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-1a cells to mount a mucosal immune response. Cellular & Molecular Immunology

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The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response

Cited by 57 publications

References 108 publications

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

Celiac disease: understanding the gluten-free diet

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

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