TY - JOUR
T1 - Phosphorylated CCAAT/enhancer binding protein β Contributes to rat HIV-related neuropathic pain
T2 - In vitro and in vivo studies
AU - Yi, Hyun
AU - Liu, Shue
AU - Kashiwagi, Yuta
AU - Ikegami, Daigo
AU - Huang, Wan
AU - Kanda, Hirotsugu
AU - Iida, Takafumi
AU - Liu, Ching Hang
AU - Takahashi, Keiya
AU - Lubarsky, David A.
AU - Hao, Shuanglin
N1 - Funding Information:
This work was supported by Grants from the U.S. National Institutes of Health NS066792 (S.H.) and DA34749 (S.H.),andbytheDepartmentofAnesthesiology,UniversityofMiamiMillerSchoolofMedicine,Miami,FL.Wethank
Funding Information:
This work was supported by Grants from the U.S. National Institutes of Health NS066792 (S.H.) and DA34749 (S.H.), andbytheDepartment of Anesthesiology, Universityof Miami Miller School of Medicine, Miami, FL. Wethank Dr. JoyJoseph(Biophysics Department, Medical Collegeof Wisconsin) for providingMito-Tempol as gift, Dr. Stephen Koslow (NIH) for checking the paper, and Dr. Frank Porreca (University of Arizona) for review of the paper.
Publisher Copyright:
© 2018 the authors.
PY - 2018/1/17
Y1 - 2018/1/17
N2 - Chronic pain is increasingly recognized as an important comorbidity of HIV-infected patients, however, the exact molecular mechanisms of HIV-related pain are still elusive. CCAAT/enhancer binding proteins (C/EBPs) are expressed in various tissues, including the CNS. C/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO 2 .- ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNFα bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO .- 2 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (amitochondria-targetedO 2 .- scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBPβ. Knock down of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBPβ. These results suggested that the pathway of TNFα/TNFRI–mtO .- 2 –pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFαin vitro and repeated intrathecal injection of recombinant TNFαin naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment.
AB - Chronic pain is increasingly recognized as an important comorbidity of HIV-infected patients, however, the exact molecular mechanisms of HIV-related pain are still elusive. CCAAT/enhancer binding proteins (C/EBPs) are expressed in various tissues, including the CNS. C/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO 2 .- ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNFα bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO .- 2 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (amitochondria-targetedO 2 .- scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBPβ. Knock down of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBPβ. These results suggested that the pathway of TNFα/TNFRI–mtO .- 2 –pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFαin vitro and repeated intrathecal injection of recombinant TNFαin naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment.
KW - Epigenetics
KW - HIV pain
KW - Mitochondrial superoxide
KW - TNFα
KW - pC/EBPβ
KW - pCREB
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U2 - 10.1523/JNEUROSCI.3647-16.2017
DO - 10.1523/JNEUROSCI.3647-16.2017
M3 - Article
C2 - 29196315
AN - SCOPUS:85040805921
VL - 38
SP - 555
EP - 574
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 3
ER -