Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn's disease and promotes experimental colitis in vivo

Holtmann, Martin; Douni, Eleni; Schutz, M.M.; Zeller, Geraldine C.; Mudter, Jonas; Lehr, Hans‐Anton; Gerspach, Jeannette; Scheurich, Peter; Galle, Peter R.; Kollias, George; Neurath, Markus F.

doi:10.1002/1521-4141(200211)32:11<3142::aid-immu3142>3.0.co;2-4

Cited by 82 publications

(62 citation statements)

References 33 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At first sight, these results seem to be in conflict with a previous report showing that TCR-a À/À mice, which lack TNFR2 exhibit an attenuated course of colitis [12]. However, in the TCR-a À/À mouse model of colitis, the disease-inducing T cells seem to be a TCR-bb expressing T-cell subset and one cannot exclude the possibility that TNFR2-mediated effects differ from the effects seen in the present study for conventional TCR-ab T cells [30].Intriguingly, overexpression of TNFR2 by CD4 + T cells has been reported previously to exacerbate disease in the CD4 + T-cell adoptive transfer model of colitis [11]. Although the pathogenic mechanisms at present remain unclear, one has to consider that overexpression of TNFR2 may substantially affect TNF-mediated effects in these cells (e.g.…”

contrasting

confidence: 61%

“…Intriguingly, overexpression of TNFR2 by CD4 + T cells has been reported previously to exacerbate disease in the CD4 + T-cell adoptive transfer model of colitis [11]. Although the pathogenic mechanisms at present remain unclear, one has to consider that overexpression of TNFR2 may substantially affect TNF-mediated effects in these cells (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is expressed predominantly by haematopoietic cells, but expression by other cell types can be induced. In particular, TNFR2 is expressed by intestinal epithelial cells during active stages of inflammation in patients with IBD and in mouse models of colitis [11,12]. TNFR2 signaling mediates NF-kB activation, leading to the transcription of several pro-inflammatory and anti-apoptotic genes.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, TNFR2 may play an important role in colonic inflammationassociated alterations of the intestinal epithelium [12]. An up-regulation of TNFR2 was also noted for lamina propria (LP) and peripheral blood T cells of patients with active CD [11]. Interestingly, it has been shown that polymorphisms in the TNFR2 gene are associated with a higher susceptibility to CD [27].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, it has been shown that polymorphisms in the TNFR2 gene are associated with a higher susceptibility to CD [27]. In the CD4 1 T-cell transfer model of colitis, overexpression of TNFR2 by CD4 1 T cells leads to an exacerbation of disease [11]. Finally, TCR-a À/À mice lacking TNFR2 exhibit an attenuated form of colitis [12].…”

mentioning

confidence: 99%

See 4 more Smart Citations

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

et al. 2009

View full text Add to dashboard Cite

TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4 + T-cell transfer model of colitis using TNFR2 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.Key words: CD4 1 T cells Á Inflammation Á Intestinal immunity Á TNF Introduction TNF plays a fundamental role in immunity and inflammation based on its pleiotropic effects on differentiation, growth and apoptotic cell death of both immune and non-immune cell subsets [1,2]. It is well established that TNF is also critically involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, MS and inflammatory bowel diseases (IBD) [3]. Monocytes and macrophages are the main producers of TNF, but T and B lymphocytes and also mast cells can produce significant amounts of TNF. Interestingly, intestinal cell lines are induced to synthesize TNF upon infection with invasive bacterial strains [4]. TNF mediates its functions by binding as a trimer to either TNF receptor (TNFR) 1 or 2. The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types. The intracellular domain of TNFR1 contains a death domain (DD) that leads to apoptosis through caspase activation. TNFR1 signaling can also mediate transcription of anti-apoptotic proteins, inflammatory cytokines and chemokines through activation of NF-kB. The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is Eur. J. Immunol. 2009. 39: 1743-1753 DOI 10.1002 Cellular immune response 1743 expressed predominantly by haematopoietic cells, but expression by other cell types can be i...

show abstract

contrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

et al. 2009

View full text Add to dashboard Cite

show abstract

Antibodies in Phase I/II/III: Targeting TNF

Holtmann¹,

Neurath²

2007

Handbook of Therapeutic Antibodies

View full text Add to dashboard Cite

Assessment of the piroxicam‐incited model of synchronized colitis in T‐cell receptor alpha chain‐deficient mice

Lange,

Bescucci,

Boras

et al. 2024

Anim Models and Exp Med

View full text Add to dashboard Cite

BackgroundA multitude of mouse models are utilized to emulate and study intestinal inflammation. T‐cell receptor alpha chain (TCRα)‐deficient mice are used as a model of spontaneous colitis that has similarities with human ulcerative colitis. However, colitis is triggered late in the life of the mouse (age: 4–5 months), and inflammation does not develop at the same time in different mice. A previously conducted study reported that the administration of the drug piroxicam triggered predictable and early colitis in TCRα‐deficient mice at the age of 6–8 weeks. However, a detailed characterization of ensuing inflammation was not provided.MethodsWe conducted an in‐depth examination of piroxicam‐triggered colitis in TCRα‐deficient mice, with emphasis on spatial histopathologic changes and analysis of expression of inflammatory markers. Furthermore, we tested amelioration of colitis with dexamethasone.ResultsWe confirmed that piroxicam induced a time‐prescribed colitis and did so in the proximal colon as well as the cecum of TCRα‐deficient mice. Piroxicam administration was observed to induce epithelial hyperplasia, goblet cell loss, and leukocyte infiltration with occasional ulceration. A Swiss roll technique was used to examine the colon and cecum in its entirety. Importantly, we observed that inflammation was multifocal segmental, with areas of tissue damage in between healthy tissue. In addition, we observed variability in the severity of inflammation among replicate animals and treatments, and that the administration of dexamethasone only partially ameliorated inflammation in the proximal colon.ConclusionsPiroxicam consistently induced multifocal segmental colitis in the proximal colon and cecum, although the degree of inflammation was reduced in the latter. Importantly, spatial variability in inflammation in the large intestine and the inter‐replicate variation in the severity of inflammation must be taken into consideration when utilizing this murine model of synchronized colitis.

show abstract

Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn's disease and promotes experimental colitis in vivo

Cited by 82 publications

References 33 publications

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

Antibodies in Phase I/II/III: Targeting TNF

Assessment of the piroxicam‐incited model of synchronized colitis in T‐cell receptor alpha chain‐deficient mice

Contact Info

Product

Resources

About

Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn's disease and promotes experimental colitis in vivo

Cited by 82 publications

References 33 publications

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

Antibodies in Phase I/II/III: Targeting TNF

Assessment of the piroxicam‐incited model of synchronized colitis in T‐cell receptor alpha chain‐deficient mice

Contact Info

Product

Resources

About

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis