CNTF regulates neurite outgrowth and neuronal migration through JAK2/STAT3 and PI3K/Akt signaling pathways of DRG explants with gp120-induced neurotoxicity in vitro.
HIV envelope glycoprotein gp120 is highly involved in HIV infection-related peripheral neuropathy, but its mechanism remains incompletely understood. The therapy of this neuropathy is still a big clinical challenge for neurologists. The organotypically cultured dorsal root ganglion (DRG) explants were used to test the neurotoxic actions of gp120 and the therapeutic effects of ciliary neurotrophic factor (CNTF) on gp120-induced neurotoxicity. The results showed that gp120 inhibited neurite outgrowth and neuronal migration from the DRG explants in a dose-dependent manner. HIV-gp120 also inhibited growth-associated protein 43 (GAP-43) expression and induced apoptosis of the migrating neurons. CNTF improved neurite outgrowth, neuronal migration, and GAP-43 expression inhibited by gp120. CNTF also rescued neuronal apoptosis induced by gp120. Either Janus kinase 2 (JAK2) inhibitor AG490 or phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002 blocked the effects of CNTF. These data imply that CNTF improved neuronal status by promoting GAP-43 expression and inhibiting apoptosis through JAK2/signal transducer and activator of transcription 3 (STAT3) and PI3K/Akt signaling pathways of DRG neurons with gp120-induced neurotoxicity. These data offered a new clue for elucidating the mechanisms of HIV infection-related peripheral neuropathy and facilitating the development of novel therapy.
Department of Rheumatology, Shandong University Qilu Hospital, Jinan 250012, China.
Huaxiang
H
Liu
Department of Histology and Embryology, Binzhou Medical College, Binzhou 256603, China.
Guixiang
G
Liu
Department of Cardiosurgery, Shandong University Qilu Hospital, Jinan 250012, China. Electronic address: yanwenbi1@126.com.
Yanwen
Y
Bi
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D006678:HIV; D015699:HIV Envelope Protein gp120 / Q000378:metabolism* / Q000633:toxicity; D053614:Janus Kinase 2 / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009924:Organ Culture Techniques; D010523:Peripheral Nervous System Diseases / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D020934:Ciliary Neurotrophic Factor; D019922:GAP-43 Protein; D015699:HIV Envelope Protein gp120; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt
Ciliary neurotrophic factor; Dorsal root ganglion; HIV; Neuropathy; Neurotoxicity; gp120