Interleukin-13 Damages Intestinal Mucosa via TWEAK and Fn14 in Mice—A Pathway Associated With Ulcerative Colitis

Kawashima, Rei; Kawamura, Yuki I.; Oshio, Tomoyuki; Son, Aoi; Yamazaki, Motomi; Hagiwara, Tokio; Okada, Toshihiko; Inagaki–Ohara, Kyoko; Wu, Ping; Szak, Suzanne; Kawamura, Yutaka; Konishi, Fumio; Miyake, Oki; Yano, Hideaki; Saitō, Yukio; Burkly, Linda C.; Dohi, Taeko

doi:10.1053/j.gastro.2011.08.040

Cited by 75 publications

(103 citation statements)

References 34 publications

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“…Only part of the mucosal explants in our control group were actually collected from patients who underwent an intestinal resection for colon cancer, and samples were taken at least 50 cm far from the tumoral mass, which makes the possibility of collecting tumour-infiltrating lymphocytes very unlikely. We can only speculate why we were not able to show enhanced IL-13 and IL-5 expression and production in UC compared to other studies [10][11][12][13]. It should be noted that when intestinal samples were collected, the large majority of CD and UC patients in our study were not on treatment with immunosuppressive drugs, which profoundly dampen cytokine secretion and may deplete T-cell subsets by induction of apoptosis.…”

Section: Discussioncontrasting

confidence: 78%

Absence of a role for interleukin‐13 in inflammatory bowel disease

et al. 2014

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IL-13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL-13 in inflammation and fibrosis in UC and Crohn's disease (CD). Intestinal biopsies and anti-CD3/CD28-or anti-CD2/CD28-stimulated lamina propria mononuclear cells from UC and CD patients and control subjects were cultured, and IL-13, IL-4, IL-5, IL-17A and IFN-γ production was measured. Mucosal IL-13-producing cells were characterised by flow cytometry. Gut explants from strictured CD, non-strictured CD and healthy donors were cultured ex vivo, and secreted IL-13, IL-1β and collagen were measured. IL-13 production by mucosal explants and activated lamina propria mononuclear cells did not differ between CD, UC and control subjects, and was at least a log lower than IFN-γ and IL-17A. IL-13-producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL-4 and IL-5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL-13, whereas IL-1β and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL-13 production. These data suggest that an anti-IL-13 Ab would not be an appropriate therapeutic strategy in inflammatory bowel disease. Keywords:Crohn's disease r Fibrosis r T helper cell type 2 r Ulcerative colitis Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Thomas T. MacDonald e-mail: t.t.macdonald@qmul.ac.uk * These authors contributed equally to this manuscript.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 370-385 Cellular immune response 371 IntroductionCrohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel disorders thought to be caused by an abnormal immune response against the normal microbial flora [1]. Until recent years, intestinal lesions in CD were thought to be the end result of a T helper cell type (Th)1 response, with overproduction of . However, more recently, two novel subsets of CD4 + T cells, namely Th17 cells, which produce the proinflammatory cytokine IL-17A, and Th1/Th17 cells, which release both IFN-γ and IL-17A, have been identified [3,4]. IL-17A is overexpressed in both CD and UC mucosa, and an increased number of Th17 and Th1/Th17 cells has been found in the lamina propria of inflammatory bowel disease patients compared with controls, suggesting that, in addition to Th1 cells, Th17 responses may play an important role in the pathogenesis of both CD and UC [5][6][7]. As opposed to CD, mucosal inflammation in UC is thought to be driven by Th2 cytokines, such as IL-5 and IL-13 [2]. IL-13 is a pleiotropic cytokine with effects on many cell types, including macrophages, epithelial cells, smooth muscle cells and neurons [8]. IL-13, produced by Th2 cells and CD1d-restricted natural killer T (NKT) cells, has been implicated in the pathogenesis of an UC-like model of...

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Section: Discussioncontrasting

confidence: 78%

Absence of a role for interleukin‐13 in inflammatory bowel disease

et al. 2014

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“…Inflammatory lesions in the gastrointestinal tract of patients with UC damage the epithelial barrier, permitting entry of bacterial products into the mucosa. 37 In patients with CD, and their first-degree relatives, increased paracellular intestinal permeability facilitates the translocation of bacterial products. 5 Hence, we were surprised to find that serum levels of LPS and sCD14 are not increased in patients with active IBD, whereas serum levels of LBP are elevated.…”

Section: Discussionmentioning

confidence: 99%

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

et al. 2013

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SummaryInflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4 + and CD8 + T lymphocytes in cycle (Ki67 + ) are increased in patients with IBD compared with these proportions in controls. CD8 + T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-c levels were elevated in resting and polyclonally activated CD4 + and CD8 + T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4 + and CD8 + T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.

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“…Similar to its name-giving cousin TNF, it contributes to the development of autoinflammatory diseases in various experimental models, including collagen induced arthritis (9, 10), myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (11-13), 2,4,6-trinitrobenzenesulfonic acid-induced colitis (14,15), and systemic lupus erythematosus-related nephritis (16) and has also been implicated in atherosclerotic plaque progression in apolipoprotein E (apoE) knock-out mice (17,18). Furthermore, TWEAK and Fn14 play a role in detrimental inflammatory and fibrotic processes associated with the repair of injured tissue after liver damage, denervation, stroke, and renal and cerebral ischemia (19 -23).…”

Section: Tnf-like Weak Inducer Of Apoptosis (Tweak)mentioning

confidence: 99%

Fibroblast Growth Factor Inducible (Fn14)-specific Antibodies Concomitantly Display Signaling Pathway-specific Agonistic and Antagonistic Activity

Salzmann

Seher

Trebing

et al. 2013

Journal of Biological Chemistry

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Background: Fn14 is a therapeutic target in various diseases. Results: Anti-Fn14 antibodies activate the alternative NFB pathway but not other Fn14-related activities induced by soluble or membrane-bound TWEAK. Fc␥R-bound anti-Fn14 antibodies, however, activate the full spectrum of Fn14-associated activities. Conclusion: Anti-Fn14 antibodies elicit agonistic activities differing from those of the natural Fn14 ligand TWEAK. Significance: These findings influence the rationale of designing Fn14-targeted therapies.

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Interleukin-13 Damages Intestinal Mucosa via TWEAK and Fn14 in Mice—A Pathway Associated With Ulcerative Colitis

Cited by 75 publications

References 34 publications

Absence of a role for interleukin‐13 in inflammatory bowel disease

Absence of a role for interleukin‐13 in inflammatory bowel disease

Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

Fibroblast Growth Factor Inducible (Fn14)-specific Antibodies Concomitantly Display Signaling Pathway-specific Agonistic and Antagonistic Activity

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Interleukin-13 Damages Intestinal Mucosa via TWEAK and Fn14 in Mice—A Pathway Associated With Ulcerative Colitis

Cited by 75 publications

References 34 publications

Absence of a role for interleukin‐13 in inflammatory bowel disease

Absence of a role for interleukin‐13 in inflammatory bowel disease

Circulating CD4+ and CD8+ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation

Fibroblast Growth Factor Inducible (Fn14)-specific Antibodies Concomitantly Display Signaling Pathway-specific Agonistic and Antagonistic Activity

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Circulating CD4⁺ and CD8⁺ T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation