Interferon Suppresses Sympathetic Neuronal Cell Death Caused by Nerve Growth Factor Deprivation

Chang, Jason Y.; Martin, David P.; Johnson, Eugene M.

doi:10.1111/j.1471-4159.1990.tb04155.x

Cited by 83 publications

(38 citation statements)

References 32 publications

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“…Sympathetic neurons were isolated from the SCG of embryonic day 21 (E21) to postnatal day 1 (P1) L ong-Evans rat pups using a procedure similar to that described by Chang et al (1990). Briefly, after anesthesia with 5% halothane, animals were decapitated, and the SCG was removed.…”

Section: Methodsmentioning

confidence: 99%

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofI_A

2000

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Electrophysiological and molecular studies have revealed considerable heterogeneity in voltage-gated K ϩ currents and in the subunits that underlie these channels in mammalian neurons. At present, however, the relationship between native K ϩ currents and cloned subunits is poorly understood. In the experiments here, a molecular genetic approach was exploited to define the molecular correlate of the fast transient outward K ϩ current, I Af , in sympathetic neurons and to explore the functional role of I Af in shaping action potential waveforms and controlling repetitive firing patterns. Using the biolistic gene gun, cDNAs encoding a dominant negative mutant Kv4.2 ␣-subunit (Kv4.2W362F) and enhanced green fluorescent protein (EGFP) were introduced into rat sympathetic neurons in vitro. Whole-cell voltage-clamp recordings obtained from EGFP-positive cells revealed that I Af is selectively eliminated in cells expressing Kv4.2W362F, demonstrating that Kv4 ␣-subunits underlie I Af in sympathetic neurons.In addition, I Af density is increased significantly in cells overexpressing wild-type Kv4.2. In cells expressing Kv4.2W362F, input resistances are increased and (current) thresholds for action potential generation are decreased, demonstrating that I Af plays a pivotal role in regulating excitability. Expression of Kv4.2W362F and elimination of I Af also alters the distribution of repetitive firing patterns observed in response to a prolonged injection of depolarizing current. The wild-type superior cervical ganglion is composed of phasic, adapting, and tonic firing neurons. Elimination of I Af increases the percentage of adapting cells by shifting phasic cells to the adapting firing pattern, and increased I Af density reduces the number of adapting cells.Key words: K ϩ channels; I A ; Kv4 ␣-subunits; Kv4.2W362F; transgenics; gene gun; neuronal excitability; repetitive firing patterns Voltage-gated potassium (K ϩ ) currents are key regulators of excitability in mammalian neurons, and in most cell types, two broad classes of voltage-gated K ϩ currents have been distinguished: (1) rapidly activating and inactivating currents, I A , and (2) delayed rectifier K ϩ currents, I K (Rudy, 1988;Storm, 1990). These are broad classifications, however, and in most mammalian neurons, multiple K ϩ current components with distinct time-and voltagedependent properties have been identified. This diversity has physiological significance because the various K ϩ currents contribute to determining the waveforms of individual action potentials and repetitive firing patterns (Pongs, 1999). Molecular cloning of K ϩ channel pore-forming ␣-and ␤-subunits has revealed considerably more heterogeneity (Coetzee et al., 1999) than was expected based on the physiology, and the relationships between these subunits and functional neuronal voltage-gated K ϩ channels are not well understood.At present, there is considerable interest in determining the molecular correlates of functional voltage-gated K ϩ channels in mammalian neurons and in defining the ro...

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Section: Methodsmentioning

confidence: 99%

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofI_A

2000

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“…The question of how IFN-␥ could interfere with such a mechanism remains. IFN-␥ was shown to exhibit neuroprotective activity in an in vitro model of neuronal cell death induced by nerve growth factor deprivation (11). In an adoptive T-cell transfer model, activated T cells with low capacity to secrete IFN-␥ induced more axonal damage than T cells with high capacity to secrete IFN-␥ (21).…”

Section: Vol 79 2005 Ifn-␥ Mediates Borna Disease Virus Clearance Fmentioning

confidence: 99%

“…On the other hand, the lack of IFN-␥ resulted in more-severe neurological disease in experimental allergic encephalomyelitis, the mouse model of the human disease multiple sclerosis (16,70). IFN-␥ was shown to prevent the apoptosis of neurons deprived of nerve growth factor (11). Nitric oxide produced by IFN-␥-induced NO synthase 2 (NOS-2) can have both neuroprotective and proapoptotic effects on neurons (3,13).…”

mentioning

confidence: 99%

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Hausmann¹,

Pagenstecher

Baur³

et al. 2005

J Virol

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Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-␥) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-␥-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-␥-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-␥-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-␥ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-␥ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

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“…Therefore, for clearance of SINV from the CNS, IFN-␥ must induce an antiviral response in neurons that are already infected, rather than protect neurons from becoming infected. The IFN-␥ receptor is constitutively expressed in many neuronal populations, and IFN-␥ can induce differentiation and improve survival, as well as induce an antiviral state (1,4,8,24,31,58,66,67,80). The importance of a direct role for IFN-␥ in control of virus replication is increasingly recognized.…”

Section: Stat-1 and Stat-5 Phosphorylation In Differentiated Ap-7 Andmentioning

confidence: 99%

Noncytolytic Clearance of Sindbis Virus Infection from Neurons by Gamma Interferon Is Dependent on Jak/Stat Signaling

Burdeinick-Kerr

Govindarajan

Griffin

2009

J Virol

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The alphavirus Sindbis virus (SINV) causes encephalomyelitis in mice byAlphaviruses in the family Togaviridae are enveloped, plusstrand, mosquito-borne RNA viruses that can cause encephalomyelitis. Sindbis virus (SINV), the prototype alphavirus, causes arthritis and rash in humans (39, 48) and encephalomyelitis in mice, a small-animal model for study of the pathogenesis of acute encephalitis (32). Age is an important determinant of outcome, and neonatal mice die within the first few days after infection, while older mice clear SINV from the central nervous system (CNS) within 6 to 8 days without signs of paralysis or neurological damage (33,40). Maturity of the infected neuron determines the level of virus replication and the susceptibility to SINV-induced cell death independent of the immune response (28,43,46,56). Immature neurons replicate SINV to higher titers and are susceptible to virus-induced apoptosis, while mature neurons are intrinsically more resistant to SINV replication and survive virus infection (3, 4, 43). Recovery from infection requires immune-mediated clearance of virus from these surviving infected neurons.Because mature neurons are terminally differentiated cells with limited capacity for regeneration, recovery that does not result in neuronal damage requires noncytolytic, rather than the more traditional cytolytic, immune mechanisms for virus clearance. Antibody is produced, T cells begin to infiltrate the CNS 3 to 4 days after infection, and virus clearance begins shortly thereafter (19,50,52). Type I interferon (IFN) is essential for initial control of virus replication (5, 6, 17, 69), and both humoral (6, 43, 77) and cellular (3, 37) arms of the adaptive immune response play important roles in clearance. Mice deficient in all components of adaptive immunity (SCID or Rag Ϫ/Ϫ ) develop persistent nonfatal infection, and passive transfer of SINV antibody results in clearance of infectious virus from the CNS and decreased viral RNA without neurologic damage, indicating an important role for antibody in noncytolytic clearance (34). However, mice deficient in antibody (MT) are able to reduce levels of SINV in the cortex and hippocampus of the brain compared to SCID mice and to clear infectious virus from the brain stem and spinal cord through local production of IFN-␥, indicating a role for T cells in clearance from some, but not all, types of neurons (3). Studies with mice deficient in production of both IFN-␥ and antibody indicate a synergistic role for these mediators in clearing SINV from the CNS, but the mechanisms are not known (5).To identify mechanisms of immune-mediated clearance, various in vitro systems have been developed. CSM14.1 neuronal cells that have been differentiated in vitro become persistently infected with SINV, and treatment with IFN-␥ results in virus clearance and improved cell survival (4, 79). Characterization of the response of infected differentiated neurons to treatment with IFN-␥ has shown a transient increase in synthesis of viral RNA and protein 6 h after tre...

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Interferon Suppresses Sympathetic Neuronal Cell Death Caused by Nerve Growth Factor Deprivation

Cited by 83 publications

References 32 publications

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofI_A

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofI_A

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Noncytolytic Clearance of Sindbis Virus Infection from Neurons by Gamma Interferon Is Dependent on Jak/Stat Signaling

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Interferon Suppresses Sympathetic Neuronal Cell Death Caused by Nerve Growth Factor Deprivation

Cited by 83 publications

References 32 publications

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofIA

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofIA

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Noncytolytic Clearance of Sindbis Virus Infection from Neurons by Gamma Interferon Is Dependent on Jak/Stat Signaling

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Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofI_A

Elimination of the Fast Transient in Superior Cervical Ganglion Neurons with Expression of KV4.2W362F: Molecular Dissection ofI_A