title: Up-regulation of CX3CL1 via Nuclear Factor-κB-dependent Histone Acetylation Is Involved in Paclitaxel-induced Peripheral Neuropathy.
abstract: BACKGROUND
  Up-regulation of CX3CL1 has been revealed to be involved in the neuropathic pain induced by nerve injury. However, whether CX3CL1 participates in the paclitaxel-induced painful peripheral neuropathy remains unknown. The aim of the current study was to elucidate the involvement of transcriptional factors nuclear factor-κB (NF-κB) and its causal interaction with CX3CL1 signaling in the paclitaxel-induced painful peripheral neuropathy.
  
  
  METHODS
  Painful peripheral neuropathy induced by paclitaxel treatment was established in adult male Sprague-Dawley rats. The von Frey test were performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were performed to understand the molecular mechanisms.
  
  
  RESULTS
  The application of paclitaxel induced an up-regulation of CX3CL1 expression in the spinal neurons, which is reduced significantly by NF-κB inhibitor ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA. Blockade of either CX3CL1 (n = 12 each) or NF-κB (n = 12 each) signaling pathway attenuated mechanical allodynia induced by paclitaxel. Chromatin immunoprecipitation further found that paclitaxel induced an increased recruitment of nuclear factor-κB (NF-κB)p65 to the Cx3cl1 promoter region. Furthermore, an increased acetylation level of H4, but not H3, in Cx3cl1 promoter region in spinal neurons was detected after paclitaxel treatment, which was reversed by inhibition of NF-κB with ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA.
  
  
  CONCLUSIONS
  These findings suggest that up-regulation of CX3CL1 via NF-κB-dependent H4 acetylation might be critical for paclitaxel-induced mechanical allodynia.
authors.affiliation: From Department of Physiology and Pain Research Center (D.L., Z.-Z.H., Y.-Z.L., J.-Y.W., Y.C., H.-Q.Z., W.-J.X.), Zhongshan Medical School, and Department of Hematology (X.-Z.Z.), the Third Affiliated Hospital, Sun Yet-Sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Dai
authors.initials: D
authors.lastname: Li
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Huang
authors.forename: Yun-Zhi
authors.initials: YZ
authors.lastname: Ling
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Wei
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.forename: Xiang-Zhong
authors.initials: XZ
authors.lastname: Zhang
authors.forename: He-Quan
authors.initials: HQ
authors.lastname: Zhu
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
mesh_terms: D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D054428:Chemokine CX3CL1 / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D006657:Histones / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017239:Paclitaxel / Q000009:adverse effects*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; D016207:Cytokines; D006657:Histones; D016328:NF-kappa B; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D013859:Thiocarbamates; D051996:Transcription Factor RelA; C020972:pyrrolidine dithiocarbamic acid; D017239:Paclitaxel