Dominant-Negative Inhibitors of Soluble TNF Attenuate Experimental Arthritis without Suppressing Innate Immunity to Infection

Zalevsky, Jonathan; Sécher, Thomas; Ezhevsky, Sergei A.; Janot, Laure; Steed, Paul M.; O’Brien, Christopher J.; Eivazi, Araz; Kung, James; Nguyen, Duc-Hanh T.; Doberstein, Stephen K.; Erard, François; Ryffel, Bernhard; Szymkowski, David E.

doi:10.4049/jimmunol.179.3.1872

Cited by 149 publications

(136 citation statements)

References 61 publications

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“…In an attempt to seek further supporting evidence, we next used XENP1595, a DN-TNF protein against soluble TNFa as reported previously. 29 As shown in Supplementary Figure S3c, XENP1595 offered perfect protection against cell death induced by zVAD and exogenous TNFa. Collectively, these data clearly demonstrate that zVAD-induced necrotic cell death in L929 cells is necroptosis that depends on autocrine production of TNFa.…”

Section: From Three Independent Experiments) (D)mentioning

confidence: 99%

zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway

et al. 2010

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It is intriguing that some pan-caspase inhibitors such as zVAD-fmk (zVAD) are capable of inducing necrotic cell death in a selected group of cells. As earlier reports from our laboratory have ruled out the original notion that zVAD-induced necrosis in mouse fibrosarcoma L929 cells was autophagic cell death, the main objective of this study was thus to determine the underlying mechanism of this form of cell death. In this study, we provided clear evidence that zVAD-induced necroptosis in L929 cells and such cell death is dependent on autocrine production of tumor necrosis factor-a (TNFa) at the transcriptional level. More importantly, we identified that activating protein-1 (AP-1), but not nuclear factor j-B, is the transcription factor controlling zVADinduced TNFa transcription. Moreover, zVAD is able to activate AP-1 through activation of two upstream mitogen-activated kinases (MAPKs), c-Jun N-terminal kinase and extracellular signal-regulated kinase. Finally, we found that protein kinase C is the important upstream signaling molecule in mediating zVAD-induced activation of MAPKs and AP-1, and subsequent autocrine production of TNFa and cell death. Data from this study reveal the molecular mechanisms underlying zVAD-induced necroptosis, an important form of programmed necrotic cell death with increasing understanding of its biological significance in health and diseases.

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Section: From Three Independent Experiments) (D)mentioning

confidence: 99%

zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway

et al. 2010

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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).…”

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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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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“…A nontreated EAE group was used as disease control. Other groups were treated with twice-weekly s.c. injections of XPro1595 (Xencor; 10 mg/kg) (17,18), etanercept (Amgen; 10 mg/kg) (19), or saline vehicle as control starting on the day of immunization.…”

Section: In Vivo Treatmentsmentioning

confidence: 99%

Altered Expression of Oligodendrocyte and Neuronal Marker Genes Predicts the Clinical Onset of Autoimmune Encephalomyelitis and Indicates the Effectiveness of Multiple Sclerosis–Directed Therapeutics

Evangelidou

Karamita

Vamvakas

et al. 2014

The Journal of Immunology

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Experimental autoimmune encephalomyelitis (EAE) is a valuable model for studying immunopathology in multiple sclerosis (MS) and for exploring the interface between autoimmune responses and CNS tissue that ultimately leads to lesion development. In this study, we measured gene expression in mouse spinal cord during myelin oligodendrocyte gp35–55 peptide–induced EAE, using quantitative RT-PCR, to identify gene markers that monitor individual hallmark pathological processes. We defined a small panel of genes whose longitudinal expression patterns provided insight into the timing, interrelationships, and mechanisms of individual disease processes and the efficacy of therapeutics for the treatment of MS. Earliest transcriptional changes were upregulation of Il17a and sharp downregulation of neuronal and oligodendrocyte marker genes preceding clinical disease onset, whereas neuroinflammatory markers progressively increased as symptoms and tissue lesions developed. EAE-induced gene-expression changes were not altered in mice deficient in IKKβ in cells of the myeloid lineage compared with controls, but the administration of a selective inhibitor of soluble TNF to mice from the day of immunization delayed changes in the expression of innate inflammation, myelin, and neuron markers from the presymptomatic phase. Proof of principle that the gene panel shows drug screening potential was obtained using a well-established MS therapeutic, glatiramer acetate. Prophylactic treatment of mice with glatiramer acetate normalized gene marker expression, and this correlated with the level of therapeutic success. These results show that neurons and oligodendrocytes are highly sensitive to CNS-directed autoimmunity before the development of clinical symptoms and immunopathology and reveal a role for soluble TNF in mediating the earliest changes in gene expression.

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Dominant-Negative Inhibitors of Soluble TNF Attenuate Experimental Arthritis without Suppressing Innate Immunity to Infection

Cited by 149 publications

References 61 publications

zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway

zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway

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

Altered Expression of Oligodendrocyte and Neuronal Marker Genes Predicts the Clinical Onset of Autoimmune Encephalomyelitis and Indicates the Effectiveness of Multiple Sclerosis–Directed Therapeutics

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