Reciprocal regulation of nuclear factor kappa B and its inhibitor ZAS3 after peripheral nerve injury.
BACKGROUND
NF-kappaB binds to the kappaB 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 kappaB or similar motif. In addition to competition for common DNA sites, in vitro experiments have shown that ZAS3 can inhibit NF-kappaB via the association with TRAF2 to inhibit the nuclear translocation of NF-kappaB. However, the physiological significance of the ZAS3-mediated inhibition of NF-kappaB 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-kappaB.


RESULTS
Immunohistochemical 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-kappaB were observed in dorsal root ganglion ipsilateral to the ligation when compared to the contralateral side.


CONCLUSIONS
ZAS3 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-kappaB, allowing Wallerian regeneration and induction of NF-kappaB-dependent gene expression, including pro-inflammatory cytokines. We propose that reciprocal changes in the expression of ZAS3 and NF-kappaB might generate neuropathic pain after peripheral nerve injury.
Wu
Lai-Chu
LC
Department of Molecular and Cellular Biochemistry, Ohio State University, OH 43210, USA. wu.39@osu.edu
Goettl
Virginia M
VM
Madiai
Francesca
F
Hackshaw
Kevin V
KV
Hussain
Syed-Rehan A
SR
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D008026:Ligation; D008297:Male; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000166:cytology; D015854:Up-Regulation; D016335:Zinc Fingers / Q000235:genetics*
D004268:DNA-Binding Proteins; C508347:Hivep3 protein, rat; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors