Abstract
BackgroundNF-κB binds to the κB motif to regulate transcription of genes involved in growth, immunity and inflammation, and plays a pivotal role in the production of pro-inflammatory cytokines after nerve injuries. The zinc finger protein ZAS3 also binds to the κB or similar motif. In addition to competition for common DNA sites, in vitro experiments have shown that ZAS3 can inhibit NF-κB via the association with TRAF2 to inhibit the nuclear translocation of NF-κB. However, the physiological significance of the ZAS3-mediated inhibition of NF-κB has not been demonstrated. The purpose of this study is to characterize ZAS3 proteins in nervous tissues and to use spinal nerve ligation, a neuropathic pain model, to demonstrate a functional relationship between ZAS3 and NF-κB.ResultsImmunohistochemical experiments show that ZAS3 is expressed in specific regions of the central and peripheral nervous system. Abundant ZAS3 expression is found in the trigeminal ganglion, hippocampal formation, dorsal root ganglia, and motoneurons. Low levels of ZAS3 expressions are also found in the cerebral cortex and in the grey matter of the spinal cord. In those nervous tissues, ZAS3 is expressed mainly in the cell bodies of neurons and astrocytes. Together with results of Western blot analyses, the data suggest that ZAS3 protein isoforms with differential cellular distribution are produced in a cell-specific manner. Further, neuropathic pain confirmed by persistent mechanical allodynia was manifested in rats seven days after L5 and L6 lumbar spinal nerve ligation. Changes in gene expression, including a decrease in ZAS3 and an increase in the p65 subunit of NF-κB were observed in dorsal root ganglion ipsilateral to the ligation when compared to the contralateral side.ConclusionZAS3 is expressed in nervous tissues involved in cognitive function and pain modulation. The down-regulation of ZAS3 after peripheral nerve injury may lead to activation of NF-κB, allowing Wallerian regeneration and induction of NF-κB-dependent gene expression, including pro-inflammatory cytokines. We propose that reciprocal changes in the expression of ZAS3 and NF-κB might generate neuropathic pain after peripheral nerve injury.
Highlights
NF-κB binds to the κB motif to regulate transcription of genes involved in growth, immunity and inflammation, and plays a pivotal role in the production of pro-inflammatory cytokines after nerve injuries
The distribution of ZAS3 proteins in the rat nervous tissues was first determined by immunohistochemical procedures using ZAS3-specific antisera, AbN and AbC
Consecutive rat coronal brain sections corresponded to the plane of bregma from -1 mm to -10 mm according to a stereotaxic atlas [27], longitudinal sections of isolated trigeminal ganglion, L3 to L6 dorsal root ganglia (DRG), and cross-sections of lumbar spinal cord were examined
Summary
NF-κB binds to the κB motif to regulate transcription of genes involved in growth, immunity and inflammation, and plays a pivotal role in the production of pro-inflammatory cytokines after nerve injuries. Peripheral nerve injury typically leads to multiple physiological alterations of the peripheral and central nervous system that includes changes in neuronal phenotype, increased excitability of spinal cord neurons, i.e., central sensitization, glial activation and disinhibition [1] These phenomena lead to the development and maintenance of neuropathic pain, through a complex web of signals and molecules that include inflammatory mediators at the site of injury, neurotransmitters, and chemokines at spinal cord synapses. A representative ZAS family member, ZAS3 ( known as Rc/ KRC/HIVEP3), associates with an adaptor molecule in the TNFα signal transduction pathway, TNF receptor-associated factor 2 (TRAF2), to inhibit the nuclear translocation and transcriptional activity of NF-κB [20,21] the interplay between ZAS3 and NF-κB may control important physiological processes, such as cell growth, apoptosis and cytokine expression
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