Soluble TNF, but not membrane TNF, is critical in LPS-induced hepatitis

Olleros, Maria-Luisa; Vesin, Dominique; Fotio, Agathe Lambou; Santiago-Raber, Marie-Laure; Tauzin, Sébastien; Szymkowski, David E.; García, Irene

doi:10.1016/j.jhep.2010.05.029

Cited by 49 publications

(42 citation statements)

References 46 publications

(72 reference statements)

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“…All results show that IL-4 had a protective effect in the BCG/ LPS model. iNOS was a critical mediator of BCG/LPS-induced liver injury that contributed to the release of pro-inflammatory cytokines [40]. The role of iNOS was to generate NO by oxidation of L-arginine to L-citrulline.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of IL-4 on Bacillus Calmette-Guerin and lipopolysaccharide induced immunological liver injury in mice

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Protective effects of IL-4 on Bacillus Calmette-Guerin and lipopolysaccharide induced immunological liver injury in mice

et al. 2011

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“…Liver proteins were analyzed by Western blotting as described previously (31). The primary antibody was either a rabbit polyclonal anti-NF-B p65 antibody (Santa Cruz Biotech) or a rabbit monoclonal anti-phosphorylated NF-B p65 antibody (Cell Signaling Tech), and the secondary antibody was a horseradish peroxidase-conjugated goat anti-rabbit antibody (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

“…Splenocytes were stimulated with medium, BCG culture filtrate antigens (CFAs; 20 g/ml), and BCG (MOI, 1), and supernatants were evaluated for IFN-␥ and nitric oxide (NO). Nitrite content, as an indicator of the NO content, was assessed by use of the Griess reagent (31).…”

Section: Methodsmentioning

confidence: 99%

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF

et al. 2015

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k Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-B activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF.T umor necrosis factor (TNF) is critical for resistance against intracellular bacterial infections; however, its dysregulation may be associated with the development of human immunopathologies (1-5). Anti-TNF therapies have shown their efficacy for the treatment of autoimmune inflammatory diseases, such as rheumatoid arthritis and Crohn's disease, and are being explored for the treatment of other severe human pathologies, such as chronic obstructive pulmonary disease (6-8). However, the complete blockade of TNF has confirmed the essential role of TNF in the control of tuberculosis (TB) infection, as treated patients develop both TB and nontuberculous mycobacterial diseases (9-12). TB is still a major health problem newly affecting in its active form nearly 9 million people every year. One-third of the global population is considered to be infected by Mycobacterium tuberculosis in a latent form (13). M. bovis BCG is used for vaccination in countries with a high TB incidence and appears to control severe forms of tuberculosis in children but fails to prevent TB in adults (14).TNF is initially synthesized as a membrane protein released under activation by infectious and inflammatory stimuli. Two types of TNF inhibitors blocking membrane and soluble TNF are currently used to treat inflammatory diseases and comprise anti-TNF antibodies (infliximab, adalimumab, certolizumab, etc.) and soluble TNF receptor 2 (sTNFR2; etanercept) (15). These drugs have distinct neutralization efficacies in human diseases, and they are associated with distinct risks of TB reactivation,...

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“…Importantly, while the ameliorating effect of XPro1595 in various animal disease models, such as acute hepatitis and inflammatory arthritis [96,97], is comparable to total TNF inhibition via etanercept, the normal immune functions are only preserved in the case of XPro1595 treatment. Thus, whereas etanercept-treated mice are highly susceptible to infection with Listeria monocytogenes, XPro1595-treated animals are largely unaffected [96].…”

Section: Stnf-selective Dominant-negative Tnf Derivativesmentioning

confidence: 99%

Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy

2015

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Deregulation of the tumor necrosis factor (TNF) plays an important role in the initiation and perpetuation of chronic inflammation and has been implicated in the development of various autoimmune diseases. Accordingly, TNF-inhibitors are successfully used for the treatment of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, total inhibition of TNF can cause severe side effects such as an increased risk of inflammation and reactivation of tuberculosis. This is likely due to the different actions of the two TNF receptors. Whereas TNFR1 predominantly promotes inflammatory signaling pathways, TNFR2 mediates immune modulatory functions and promotes tissue homeostasis and regeneration. Therefore, the specific blockage of TNFR1 signaling, either by direct inhibition with TNFR1-selective antagonists or by targeting soluble TNF, which predominantly activates TNFR1, may prevent the detrimental effects associated with total TNF-inhibitors and constitute a next-generation approach to interfere with TNF.

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Soluble TNF, but not membrane TNF, is critical in LPS-induced hepatitis

Cited by 49 publications

References 46 publications

Protective effects of IL-4 on Bacillus Calmette-Guerin and lipopolysaccharide induced immunological liver injury in mice

Protective effects of IL-4 on Bacillus Calmette-Guerin and lipopolysaccharide induced immunological liver injury in mice

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF

Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy

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