Tumor Necrosis Factor-α: a Neuromodulator in the CNS

Pan, Weihong; Zadina, James E.; Harlan, Richard E.; Weber, Joseph T.; Banks, William A.; Kastin, Abba J.

doi:10.1016/s0149-7634(96)00047-4

Cited by 164 publications

(96 citation statements)

References 107 publications

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“…TNF-α may affect a variety of neuronal functions, including membrane potential and second-messenger signaling pathways (Pan et al 1997, Munoz-Fernandez andFresno 1998). Furthermore, TNF-α has been implicated in the regulation of feeding, sleeping, and other autonomic, neuroendocrine-related functions (Plata-Salaman et al 1988, Pan et al 1997, Krueger et al 1998. Increased levels of TNF-α, as well as of other cytokines, have been well documented in the pathophysiology of disease.…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss

Oishi

Zheng

Hill

et al. 2013

JARO

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Exogenous tumor necrosis factor-alpha (TNF-α) plays a role in auditory hair cell death by altering the expression of apoptosis-related genes in response to noxious stimuli. Little is known, however, about the function of TNF-α in normal hair cell physiology. We, therefore, investigated the cochlear morphology and auditory function of TNF-α-deficient mice. Auditory evoked brainstem response showed significantly higher thresholds, especially at higher frequencies, in 1-month-old TNF-α −/− mice as compared to TNF-α +/− and wild type (WT); hearing loss did not progress further from 1 to 4 months of age. There was no difference in the gross morphology of the organ of Corti, lateral wall, and spiral ganglion cells in TNF-α −/− mice compared to WT mice at 4 months of age, nor were there differences in the anatomy of the auditory ossicles. Outer hair cells were completely intact in surface preparations of the organ of Corti of TNF-α −/− mice, and synaptic ribbon counts of TNF-α −/− and WT mice at 4 months of age were similar. Reduced amplitudes of distortion product otoacoustic emissions, however, indicated dysfunction of outer hair cells in TNF-α −/− mice. Scanning electron microscopy revealed that stereocilia were sporadically absent in the basal turn and distorted in the middle turn. In summary, our results demonstrate that TNF-α-mutant mice exhibit early hearing loss, especially at higher frequencies, and that loss or malformation of the stereocilia of outer hair cells appears to be a contributing factor.

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Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss

Oishi

Zheng

Hill

et al. 2013

JARO

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“…including the development of tissues and the coordinate activation of immune responses, as well as in the onset and progress of pathological conditions (1)(2)(3)(4). Most of these actions are exerted by TNF-␣ via its ability to induce cell death via apoptosis.…”

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confidence: 99%

Activation of the Endothelial Nitric-oxide Synthase by Tumor Necrosis Factor-α

Bulotta

Barsacchi

Rotiroti

et al. 2001

Journal of Biological Chemistry

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Cell death via apoptosis induced by tumor necrosis factor-␣ (TNF-␣) plays an important role in many physiological and pathological conditions. The signal transduction pathway activated by this cytokine is known to be regulated by several intracellular messengers. In particular, in many systems nitric oxide (NO) has been shown to protect cells from TNF-␣-induced apoptosis. However, whether NO can be generated by the cytokine to down-regulate its own apoptotic program has never been studied. We have addressed this question in HeLa Tet-off cell clones stably transfected with the endothelial NO synthase under a tetracycline-responsive promoter. Endothelial NO synthase, induced about 100-fold in these cells by removal of the antibiotic, retained the characteristics of the native enzyme of endothelial cells, both in terms of intracellular localization and functional activity. Expression of the endothelial NO synthase was sufficient to protect from TNF-␣-induced apoptosis. This protection was mediated by the generation of NO. TNF-␣ itself stimulated endothelial NO synthase activity to generate NO through a pathway involving its lipid messenger, ceramide. Our results identify a novel mechanism of regulation of a signal transduction pathway activated by death receptors and suggest that NO may constitute a built-in mechanism by which TNF-␣ controls its own apoptotic program.

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“…TNF has dual actions in the CNS [15]. On the one hand, after SCI it is involved in inflammation, myelin destruction, apoptotic neuronal cell death, and astrocyte toxicity.…”

Section: Tumor Necrosis Factor-α (Tnf) In Sci 2a Tnf In Cns Inflammamentioning

confidence: 99%

Cytokine Transport Across the Injured Blood-Spinal Cord Barrier

Pan¹,

Kastin²

2008

CPD

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Spinal cord injury (SCI) induces dynamic changes of the blood-spinal cord barrier and even the more distant blood-brain barrier. Besides an immediate increase of paracellular permeability resulting from the direct impact of the injury, the transport systems for selective cytokines undergo regulatory changes. Since many of the transported molecules play essential roles in neuroregeneration, we propose that this altered peripheral tissue / CNS interaction benefits remodeling of the spinal cord and functional recovery after SCI. This review examines the transport of cytokines and neurotrophic factors into the spinal cord, emphasizing the upregulation of two cytokines -tumor necrosis factor α (TNF) and leukemia inhibitory factor (LIF) -during the course of SCI. The increased transport of TNF and LIF after SCI remains saturable and does not coincide with generalized BBB disruption, highlighting a pivotal regulatory role for the bloodspinal cord barrier.

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Tumor Necrosis Factor-α: a Neuromodulator in the CNS

Cited by 164 publications

References 107 publications

Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss

Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss

Activation of the Endothelial Nitric-oxide Synthase by Tumor Necrosis Factor-α

Cytokine Transport Across the Injured Blood-Spinal Cord Barrier

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