title: The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway.
abstract: Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-α and the biological effects, produced by interaction of IGF-1 and TNF-α, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-α challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-α (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-α (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-α (10 ng/mL) challenge. In contrast, lower concentration of TNF-α (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These data imply that IGF-1 counteracts the toxic effect of higher concentration of TNF-α, while potentiates the growth-promoting effect of lower concentration of TNF-α, with the node for TNF-α and IGF-1 interaction being the PI3K/Akt/S6K signaling pathway. This study is helpful for interpretation of the association of IGF-1 with TNF-α and the neurobiological effects elicited by interaction of IGF-1 and TNF-α in neurological disorders.
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Shandong University School of Public Health, Jinan, 250012, China.
authors.forename: Meishuo
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Department of Rheumatology, Shandong University Qilu Hospital, Jinan, 250012, China.
authors.forename: Huaxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China. zli@sdu.edu.cn.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Li
mesh_terms: D051700:Activating Transcription Factor 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019922:GAP-43 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D000071446:Neuronal Outgrowth / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D019922:GAP-43 Protein; D014409:Tumor Necrosis Factor-alpha; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2
keywords: Activating transcription factor 3; Dorsal root ganglion; Growth-associated protein 43; Insulin-like growth factor-1; Neurite outgrowth; Neuron; Tumor necrosis factor-α