CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice

Obermeier, Florian; Dunger, Nadja; Deml, Ludwig; Herfarth, Hans H; Schölmerich, Jürgen; Falk, Werner

doi:10.1002/1521-4141(200207)32:7<2084::aid-immu2084>3.0.co;2-q

Cited by 119 publications

(81 citation statements)

References 36 publications

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“…Indeed, polymorphisms in TLR9 have been associated with Crohn's disease (37) and TLR9 signaling has been shown essential in mediating the anti-inflammatory effects of probiotics and CpG-ODNs in models of induced experimental colitis (38,39). On the contrary, a severe exacerbation of inflammatory disease was induced by CpG-ODN when treatment was performed after the establishment of colitis (40) and a reduced inflammatory response to bacterial sepsis has been recently observed in TLR9 Ϫ/Ϫ mice (21). An explanation for this apparent discrepancy in the control of intestinal inflammation by TLR9 is suggested by a recent study which demonstrated the expression of TLR9 on both apical and basolateral surface of intestinal epithelial cells and a different response to apical or basolateral signals: while apical stimulation of TLR9 limited inflammatory response and confers tolerance to other TLR agonists, basolateral stimulation induced inflammation (17).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Calcaterra

Sfondrini²,

Rossini³

et al. 2008

The Journal of Immunology

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Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9 ؊/؊ ) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4 ؊/؊ ) mice. The reduced mortality and morbidity in TLR9 ؊/؊ mice related with reduced stimulatory activity of TLR9 ؊/؊ spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9 ؉/؉ into TLR9 ؊/؊ and TLR9 ؊/؊ into TLR9؉/؉ chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9 ؉/؉ cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.

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Section: Discussionmentioning

confidence: 99%

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Calcaterra

Sfondrini²,

Rossini³

et al. 2008

The Journal of Immunology

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“…15,16 Body weight was recorded daily. For therapeutic studies, mice with DSS-induced acute colitis received 100 lg of affinity-purified anti-mouse LIGHT mAbs (i.p.…”

Section: Induction and Treatment Of Colitismentioning

confidence: 99%

Neutralization of LIGHT ameliorates acute dextran sodium sulphate‐induced intestinal inflammation

et al. 2009

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Summary Emerging data indicate that alterations in the expression of tumour necrosis factor (TNF) superfamily members play a crucial role in the pathogenesis of intestinal inflammation. Recent results demonstrated that sustained transgenic expression of lymphotoxin‐like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT; TNFSF14) induced severe intestinal inflammation, suggesting a specific role of LIGHT‐mediated signalling to the intestinal compartment. In order to dissect the role of LIGHT in intestinal inflammation, we used LIGHT‐deficient mice in the mouse model of acute dextran sodium sulphate‐induced colitis. Interestingly, LIGHT‐deficient mice were characterized by strongly reduced signs of intestinal inflammation compared with wild‐type mice in this experimental model. Determination of mouse LIGHT mRNA expression in colon tissues of wild‐type mice revealed a strong induction of mouse LIGHT mRNA expression during acute DSS‐induced colitis. We therefore generated anti‐mouse LIGHT monoclonal antibodies in LIGHT‐deficient mice which bind specifically to LIGHT and are capable of neutralizing the activity of LIGHT in vitro and in vivo. With these antibodies, we demonstrated that neutralization of LIGHT during acute DSS‐induced colitis resulted in reduced signs of intestinal inflammation. These data suggest that LIGHT is an important mediator in intestinal inflammation and may serve as a new target for therapeutic intervention.

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“…For induction of chronic colitis, BALB/c mice received four cycles of DSS treatment as described [60]. Each cycle consisted of 3% DSS in drinking water for 7 days, followed by a 10-day interval with normal drinking water.…”

Section: Induction and Treatment Of Chronic Dss-induced Colitismentioning

confidence: 99%

“…The distal third of the colon was removed and used for histological analysis as described before [60,63]. Three sections were evaluated obtained each at a 100-lm distance.…”

Section: Assessment Of Histological Scorementioning

confidence: 99%

IL‐15 protects intestinal epithelial cells

et al. 2006

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IL‐15, a T‐cell growth factor, has been shown to be increased in inflammatory bowel disease (IBD). It has been suggested that neutralization of IL‐15 could protect from T cell‐dependent autoimmune inflammation. On the other hand, an anti‐apoptotic effect of IL‐15 has been demonstrated in kidney epithelial cells during nephritis. We therefore tested the role of IL‐15 in two different experimental models of colitis in vivo, and in models of intestinal epithelial cell (IEC) apoptosis in vitro. IL‐15 blockade in chronic dextran sulphate sodium‐induced colitis resulted in aggravation of the disease with a significantly 2.1‐fold increased epithelial damage score compared to controls. TUNEL staining clearly revealed increased apoptosis. IL‐6, TNF and IFN‐γ secretion by mesenteric lymph node cells were increased. In the T cell‐dependent SCID transfer model of colitis IL‐15 neutralization reduced the inflammatory infiltration and proinflammatory cytokine production. Despite that, the intestinal epithelial damage was not reduced. In vitro, IL‐15 pre‐incubation prevented up to 75% of CH11 antibody‐induced apoptosis in SW‐480 cells and reduced caspase‐3 activity. According to this, endogenously produced IL‐15 in chronic colitis does not only act as a proinflammatory cytokine but has at the same time the potential to reduce mucosal damage by preventing IEC apoptosis.

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CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice

Cited by 119 publications

References 36 publications

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Neutralization of LIGHT ameliorates acute dextran sodium sulphate‐induced intestinal inflammation

IL‐15 protects intestinal epithelial cells

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