Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants

Steed, Paul M.; Tansey, Malú G.; Zalevsky, Jonathan; Zhukovsky, Eugene A.; Desjarlais, John R.; Szymkowski, David E.; Abbott, Christina M.; Carmichael, David F.; Chan, Cheryl; Cherry, Lisa; Cheung, Peter; Chirino, Arthur J.; Chung, H.; Doberstein, Stephen K.; Eivazi, Araz; Filikov, Anton V.; Gao, Sarah X.; Hubert, R; Hwang, Marian Y.; Hyun, Linus; Kashi, Sandhya; Kim, Alice; Kim, Esther; Kung, James; Martinez, Sabrina P.; Muchhal, T. Umesh S.; Nguyen, Duc-Hanh T.; O’Brien, Christopher J.; O'Keefe, Donald O.; Singer, Karen L.; Vafa, Omid; Vielmetter, Jost; Yoder, Sean C.; Dahiyat, Bassil I.

doi:10.1126/science.1081297

Cited by 228 publications

(164 citation statements)

References 24 publications

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“…To investigate whether the observed peripheral elevation of TNF-α is important for synaptic alterations in the somatosensory cortex, we examined the effect of chronic inhibition of TNF-α on dendritic spine and axonal bouton plasticity by applying a dominant negative form of TNF-α (DN-TNF) for 1 wk (10 mg/kg body weight, 1-2 times per day) after MOG immunization. DN-TNF selectively decreases activation of TNFR1 by blocking the effects of circulating soluble TNF-α (35,36). This inhibition resulted in a significant reduction in the rate of spine elimination and formation in MOG-immunized mice (elimination: 4.6 ± 0.6%; formation: 4.8 ± 0.7%, 743 spines, five animals) (Fig.…”

Section: Peripheral Production Of Tnf-α Is Important For Early Synapticmentioning

confidence: 99%

“…TNFR1 activation also initiates the JNK pathway thought to be involved in dendritic cytoskeleton stability via regulation of microtubules (16). A dominant negative TNF inhibitor, XPro1595, blocks the effects of solTNF to selectively decrease the activation of TNFR1 (35,36). Recently, decreased activation of TNFR1 via XPro1595 has been shown to promote axonal integrity and improve clinical outcome of mice with EAE (10).…”

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Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

Yang

Parkhurst

Hayes

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Sensory abnormalities such as numbness and paresthesias are often the earliest symptoms in neuroinflammatory diseases including multiple sclerosis. The increased production of various cytokines occurs in the early stages of neuroinflammation and could have detrimental effects on the central nervous system, thereby contributing to sensory and cognitive deficits. However, it remains unknown whether and when elevation of cytokines causes changes in brain structure and function under inflammatory conditions. To address this question, we used a mouse model for experimental autoimmune encephalomyelitis (EAE) to examine the effect of inflammation and cytokine elevation on synaptic connections in the primary somatosensory cortex. Using in vivo two-photon microscopy, we found that the elimination and formation rates of dendritic spines and axonal boutons increased within 7 d of EAE induction-several days before the onset of paralysis-and continued to rise during the course of the disease. This synaptic instability occurred before T-cell infiltration and microglial activation in the central nervous system and was in conjunction with peripheral, but not central, production of TNF-α. Peripheral administration of a soluble TNF inhibitor prevented abnormal turnover of dendritic spines and axonal boutons in presymptomatic EAE mice. These findings indicate that peripheral production of TNF-α is a key mediator of synaptic instability in the primary somatosensory cortex and may contribute to sensory and cognitive deficits seen in autoimmune diseases.

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Section: Peripheral Production Of Tnf-α Is Important For Early Synapticmentioning

confidence: 99%

mentioning

confidence: 99%

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

Yang

Parkhurst

Hayes

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, a splice variant of BAFF (DBAFF) inhibits regular BAFF by forming inactive heteromers [12]. This strategy could be exploited to poison endogenous BAFF with exogenously added recombinant BAFF mutants [13], and could be used to intervene in autoimmune and other conditions in which BAFF is produced in excess. BAFF can also heterotrimerize with APRIL in undefined stoichiometry [14], although this process appears to be far less efficient than the heterotrimerization of lymphotoxin a 1 b 2 , a well-characterized heterotrimer of the TNF family.…”

Section: The Interactions Of Baff and April With Their Receptors And mentioning

confidence: 99%

The role of APRIL and BAFF in lymphocyte activation

Schneider

2005

Current Opinion in Immunology

304

249

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“…DN TNF variants are novel TNF-␣-blocking agents engineered to structurally resemble TNF-␣ but contain mutations that alter their ability to bind and signal through TNF receptors (35). DN TNF peptides inhibit TNF-␣-mediated signal transduction by rapidly heterotrimerizing with soluble TNF-␣, sequestering native ligand into inactive complexes.…”

Section: Ffas Increase the Secretion Of Tnf-␣ By 3t3-l1mentioning

confidence: 99%

JNK and Tumor Necrosis Factor-α Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes

Nguyen

Satoh

Favelyukis

et al. 2005

Journal of Biological Chemistry

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379

268

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Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3-L1 adipocytes with a mixture of free fatty acids (FFAs) to investigate the molecular mechanisms underlying fat-induced insulin resistance. FFA treatment impaired insulin receptor-mediated signal transduction and decreased insulin-stimulated GLUT4 translocation and glucose transport. FFAs activated the stress/inflammatory kinases c-Jun N-terminal kinase (JNK) and IKK␤, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-␣, and decreased secretion of adiponectin into the medium. RNA interference-mediated down-regulation of JNK blocked JNK activation and prevented most of the FFA-induced defects in insulin action. Blockade of TNF-␣ signaling with neutralizing antibodies to TNF-␣ or its receptors or with a dominant negative TNF-␣ peptide had a partial effect to inhibit FFA-induced cellular insulin resistance. We found that JNK activation by FFAs was not inhibited by blocking TNF-␣ signaling, whereas the FFA-induced increase in TNF-␣ secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-␣-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-␣ is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance.

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Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants

Cited by 228 publications

References 24 publications

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

The role of APRIL and BAFF in lymphocyte activation

JNK and Tumor Necrosis Factor-α Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes

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