Tumor necrosis factor: an apoptosis JuNKie?

Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell (Impact Factor: 33.12). 03/2004; 116(4):491-7.
Source: PubMed

ABSTRACT TNF's main function is to stimulate inflammation by turning on gene transcription through the IKK/NFkappaB and JNK/AP-1 signaling cascades. TNF also can trigger apoptosis through caspase-8, but the role and underlying mechanism of this activity are not fully understood. Here, we review recent data on the role of JNK in the regulation of TNF-dependent apoptosis and discuss what is known so far about how cells decide whether to live or die in response to TNF.

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    ABSTRACT: Background Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood¿brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-¿ is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases.Objective To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain.Methods Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-¿ expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining.ResultsThe LPS¿+¿HI group had significantly greater up-regulation of activated microglia, TNF-¿ and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS¿+¿HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-¿ inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI.ConclusionTNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS-sensitized HI in the immature brain.
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    ABSTRACT: Background Glaucoma is an optic neuropathy that is characterized by the loss of retinal ganglion cells (RGCs) initiated by damage to axons in the optic nerve. The degeneration and death of RGCs has been thought to occur in two waves. The first is axogenic, caused by direct insult to the axon. The second is somatic, and is thought to be caused by the production of inflammatory cytokines from the activated retinal innate immune cells. One of the cytokines consistently linked to glaucoma and RGC damage has been TNF¿. Despite strong evidence implicating this protein in neurodegeneration, a direct injection of TNF¿ does not mimic the rapid loss of RGCs observed after acute optic nerve trauma or exposure to excitotoxins. This suggests that our understanding of TNF¿ signaling is incomplete.MethodsRGC death was induced by optic nerve crush in mice. The role of TNF¿ in this process was examined by quantitative PCR of Tnf¿ gene expression, and quantification of cell loss in Tnf¿ ¿/¿ mice or in wild-type animals receiving an intraocular injection of exongenous TNF¿ either before or after crush. Signaling pathways downstream of TNF¿ were examined by immunolabeling for JUN protein accumulation or activation of EGFP expression in NF¿B reporter mice.ResultsOptic nerve crush caused a modest increase in Tnf¿ gene expression, with kinetics similar to the activation of both macroglia and microglia. A pre-injection of TNF¿ attenuated ganglion cell loss after crush, while ganglion cell loss was more severe in Tnf¿ ¿/¿ mice. Conversely, over the long term, a single exposure to TNF¿ induced extrinsic apoptosis in RGCs. Müller cells responded to exogenous TNF¿ by accumulating JUN and activating NF¿B.Conclusion Early after optic nerve crush, TNF¿ appears to have a protective role for RGCs, which may be mediated through Müller cells.
    Journal of Neuroinflammation 11/2014; 11(1):194. DOI:10.1186/s12974-014-0194-3 · 4.90 Impact Factor
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    ABSTRACT: Sustained inflammation may increase the susceptibility of hepatocytes to apoptotic cell death and therefore exacerbate liver damage. Here we report that the pro-inflammatory cytokine IL-1β sensitizes primary murine hepatocytes to Fas ligand (FasL)-induced caspase-3/-7 activity. This process was dependent on JNK1/2 and the BH3-only proteins Bim and Bid. Mathematical modeling revealed that incubation of hepatocytes with IL-1β depleted the anti-apoptotic Bcl-2 protein pool and thus shifted hepatocytes to mitochondrial type II apoptosis following Fas activation. As a consequence, IL-1β and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1β pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1β and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1β was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF-κB DNA binding was increased in response to IL-1β plus FasL and gene-expression profiling of NF-κB regulated genes revealed a transcriptional and translational upregulation of the caspase-8 inhibitor A20. A mathematical model was developed to explain the contradictious occurrence of both increased caspase-3/-7 activity and elevated cell viability by including a heterogeneous distribution of Bcl-2 proteins and variations in Fas signaling resulting in different subpopulations of hepatocytes.
    PLoS ONE 12/2014; 9(12):e115603. DOI:10.1371/journal.pone.0115603 · 3.53 Impact Factor

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