Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohnʼs disease

Santaolalla, Rebeca; Mañé, Josep; Pedrosa, E.; Lorén, Violeta; Fernández‐Bañares, Fernando; Mallolas, Judith; Carrasco, Anna; Salas, Antonio; Rosinach, Mercé; Forné, Montserrat; Espinós, Jorge C.; Loras, Carme; Donovan, Michael; Puig, Pere; Mañosa, Míriam; Gassull, Miquel A.; Viver, Josep Maria

doi:10.1002/ibd.21507

Cited by 24 publications

(18 citation statements)

References 36 publications

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“…Although there was low transcriptional expression of Bcl2 in the ICD group, no differences were observed with regard to Bcl-2 protein expression, as analyzed by immunohistochemistry in this group. These findings reinforce the data of Itoh et al [10] and Santaolalla et al [17], who associated the defective apoptosis in the lamina propria to the Bax-related pathways.…”

Section: Discussionsupporting

confidence: 91%

“…In this situation, the remaining cells may be the ones that show low rate of apoptosis and high rate of proliferation in order to recover the affected area and restore function. Concerning the decreased apoptosis in lamina propria cells of CD compared to the controls, and the fact that part of these cells are immune cells, this confirms previous published results in the literature [10], [17].…”

Section: Discussionsupporting

confidence: 90%

“…[14]–[16] Reports show that the T cells of CD mucosa exhibit resistance to a variety of signals that induce apoptosis, including the differential expression of proteins from the Bcl-2 family and differences in the ratio between pro and anti-apoptotic proteins [10], [17], suggesting that apoptosis may be one of the mechanisms involved in CD pathophysiology. Furthermore, defective apoptosis in immune cells, such as macrophages and neutrophils, has been reported [18], [19].…”

Section: Introductionmentioning

confidence: 99%

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Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients

et al. 2014

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BackgroundCrohn’s disease (CD) is associated with complex pathogenic pathways involving defects in apoptosis mechanisms. Recently, mesenteric adipose tissue (MAT) has been associated with CD ethiopathology, since adipose thickening is detected close to the affected intestinal area. However, the potential role of altered apoptosis in MAT of CD has not been addressed.AimsTo evaluate apoptosis in the intestinal mucosa and MAT of patients with CD.MethodsSamples of intestinal mucosa and MAT from patients with ileocecal CD and from non-inflammatory bowel diseases patients (controls) were studied. Apoptosis was assessed by TUNEL assay and correlated with the adipocytes histological morphometric analysis. The transcriptional and protein analysis of selected genes and proteins related to apoptosis were determined.ResultsTUNEL assay showed fewer apoptotic cells in CD, when compared to the control groups, both in the intestinal mucosa and in MAT. In addition, the number of apoptotic cells (TUNEL) correlated significantly with the area and perimeter of the adipose cells in MAT. Transcriptomic and proteomic analysis reveal a significantly lower transcript and protein levels of Bax in the intestinal mucosa of CD, compared to the controls; low protein levels of Bax were found localized in the lamina propria and not in the epithelium of this tissue. Furthermore, higher level of Bcl-2 and low level of Caspase 3 were seen in the MAT of CD patients.ConclusionThe defective apoptosis in MAT may explain the singular morphological characteristics of this tissue in CD, which may be implicated in the pathophysiology of the disease.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients

et al. 2014

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“…Although IRF-1 Ϫ/Ϫ and IL-10 Ϫ/Ϫ mice are more susceptible to DSS-induced colitis [38,55], IRF-1 signaling and IL-10 were found to be dispensable for APP-mediated protection. The finding that APP can confer protection against colitis in the absence of IL-10 is particularly intriguing, as patients with severe Crohn's disease are defective in IL-10 production [56], and IL-10 expression is impaired in the intestinal mucosa of Crohn's disease patients who failed to respond to steroid therapy [57]. Thus, APP uses an IL-10-independent pathway to provide protection against IBD, implicating APP as a potential benefit to complement therapies targeting IL-10, which can be ineffective.…”

Section: Discussionmentioning

confidence: 97%

Apple polyphenols require T cells to ameliorate dextran sulfate sodium-induced colitis and dampen proinflammatory cytokine expression

Skyberg

Robison

Golden

et al. 2011

Journal of Leukocyte Biology

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Human IBD, including UC and Crohn's disease, is characterized by a chronic, relapsing, and remitting condition that exhibits various features of immunological inflammation and affects at least one/1000 people in Western countries. Polyphenol extracts from a variety of plants have been shown to have immunomodulatory and anti-inflammatory effects. In this study, treatment with APP was investigated to ameliorate chemically induced colitis. Oral but not peritoneal administration of APP during colitis induction significantly protected C57BL/6 mice against disease, as evidenced by the lack of weight loss, colonic inflammation, and shortening of the colon. APP administration dampened the mRNA expression of IL-1β, TNF-α, IL-6, IL-17, IL-22, CXCL9, CXCL10, CXCL11, and IFN-γ in the colons of mice with colitis. APP-mediated protection requires T cells, as protection was abated in Rag-1(-/-) or TCRα(-/-) mice but not in IL-10(-/-), IRF-1(-/-), μMT, or TCRδ(-/-) mice. Administration of APP during colitis to TCRα(-/-) mice actually enhanced proinflammatory cytokine expression, further demonstrating a requirement for TCRαβ cells in APP-mediated protection. APP treatment also inhibited CXCR3 expression by TCRαβ cells, but not B or NK cells, in the colons of mice with colitis; however, depletion of CD4(+) or CD8(+) T cells alone did not abolish APP-mediated protection. Collectively, these results show that oral administration of APP protects against experimental colitis and diminishes proinflammatory cytokine expression via T cells.

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“…However, the colonic IL-10 expression profile in patients with IBD is controversial. Most reports indicate that mucosal levels of IL-10 are increased in UC[27,35], but normal[28], decreased[36,37] and elevated[38,39] mucosal IL-10 levels are reported for CD. Recent studies have demonstrated that polymorphisms of the IL-10 gene are correlated with the development of UC and CD[40].…”

Section: Discussionmentioning

confidence: 99%

Recombinant adeno-associated virus carrying thymosin β₄suppresses experimental colitis in mice

Zheng¹,

Lv²,

Li³

et al. 2017

WJG

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AIMTo investigate the protective effect of a recombinant adeno-associated virus carrying thymosin β4 (AAV-Tβ4) on murine colitis via intracolonic administration.METHODSAAV-Tβ4 was prepared and intracolonically used to mediate the secretory expression of Tβ4 in mouse colons. Dextran sulfate sodium (DSS) was applied to induce the murine ulcerative colitis, and 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to establish a mouse colitis model resembling Crohn’s disease. The disease severity and colon injuries were observed and graded to reveal the effects of AAV-Tβ4 on colitis. The activities of myeloperoxidase (MPO) and superoxide dismutase (SOD) and the content of malondialdehyde (MDA) were determined using biochemical assays. Colonic levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-10 were measured using ELISA, and mucosal epithelial cell apoptosis and proliferation were detected by TUNEL assay and immunochemistry, respectively.RESULTSRecombinant AAVs efficiently delivered LacZ and Tβ4 into the colonic tissues of the mice, and AAV-Tβ4 led to a strong expression of Tβ4 in mouse colons. In both the DSS and TNBS colitis models, AAV-Tβ4-treated mice displayed distinctly attenuated colon injuries and reduced apoptosis rate of colonic mucosal epithelia. AAV-Tβ4 significantly reduced inflammatory cell infiltrations and relieved oxidative stress in the inflamed colons of the mice, as evidenced by decreases in MPO activity and MDA content and increases in SOD activity. AAV-Tβ4 also modulated colonic TNF-α, IL-1β and IL-10 levels and suppressed the compensatory proliferation of colonic epithelial cells in DSS- and TNBS-treated mice.CONCLUSIONTβ4 exerts a protective effect on murine colitis, indicating that AAV-Tβ4 could potentially be developed into a promising agent for the therapy of inflammatory bowel diseases.

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Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohnʼs disease

Cited by 24 publications

References 36 publications

Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients

Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients

Apple polyphenols require T cells to ameliorate dextran sulfate sodium-induced colitis and dampen proinflammatory cytokine expression

Recombinant adeno-associated virus carrying thymosin β₄suppresses experimental colitis in mice

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Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohnʼs disease

Cited by 24 publications

References 36 publications

Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients

Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients

Apple polyphenols require T cells to ameliorate dextran sulfate sodium-induced colitis and dampen proinflammatory cytokine expression

Recombinant adeno-associated virus carrying thymosin β4suppresses experimental colitis in mice

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Product

Resources

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Recombinant adeno-associated virus carrying thymosin β₄suppresses experimental colitis in mice