Functionally Enhanced siRNA Targeting TNFα Attenuates DSS-induced Colitis and TLR-mediated Immunostimulation in Mice

Ocampo, Sandra M.; Romero, Carolina; Aviñó, Anna; Burgueño, Joan F.; Gassull, M. A.; Bermúdez, Jordi; Eritja, Ramón; Fernández, Ester; Perales, José C.

doi:10.1038/mt.2011.236

Cited by 25 publications

(17 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absence or inhibition of TNF activity ameliorates disease progression in different experimen-tal IBD models and in human patients. Treatment with a TNF neutralizing antibody, a locally active TNF inhibitor, antisense oligonucleotides and siRNA molecules specific for TNF were shown to be effective in the DSS-induced colitis model (Dharmani et al, 2011;Murthy et al, 2002;Myers et al, 2003;Ocampo et al, 2012). As expected, we observed that MMP13 À/À mice were less sensitive to DSS-induced colitis than MMP13 þ/þ mice and that this was correlated with reduced bioactive TNF levels.…”

Section: Discussionsupporting

confidence: 80%

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

2014

Health and the Gut

View full text Add to dashboard Cite

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13 À/À mice display a strong protection in LPS-and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13 À/À mice compared to MMP13 þ/þ mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential.

show abstract

Section: Discussionsupporting

confidence: 80%

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

2014

Health and the Gut

View full text Add to dashboard Cite

show abstract

“…The absence or inhibition of TNF activity ameliorates disease progression in different experimental IBD models and in human patients. Treatment with a TNF neutralizing antibody, a locally active TNF inhibitor, antisense oligonucleotides and siRNA molecules specific for TNF were shown to be effective in the DSS‐induced colitis model (Dharmani et al, ; Murthy et al, ; Myers et al, ; Ocampo et al, ). As expected, we observed that MMP13 −/− mice were less sensitive to DSS‐induced colitis than MMP13 +/+ mice and that this was correlated with reduced bioactive TNF levels.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Vandenbroucke¹,

Dejonckheere²,

Hauwermeiren³

et al. 2013

EMBO Mol Med

121

View full text Add to dashboard Cite

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13−/− mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13−/− mice compared to MMP13+/+ mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13−/− mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential.

show abstract

“…Lipoplex-siRNA-2 is an enema containing liposomal, chemically modified siRNA against TNF-α [ 135 ]. Chemically modifying siRNA may increase the silencing capacity, resistance to degradation or both.…”

Section: Preclinical Studies On Local Tnf-α Inhibitionmentioning

confidence: 99%

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

et al. 2020

View full text Add to dashboard Cite

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.

show abstract

Functionally Enhanced siRNA Targeting TNFα Attenuates DSS-induced Colitis and TLR-mediated Immunostimulation in Mice

Cited by 25 publications

References 46 publications

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

Contact Info

Product

Resources

About