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The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway.
Neurochem Res. 2017 May; 42(5):1403-1421.NR

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+Show Affiliations

Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China.Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China.Shandong University School of Public Health, Jinan, 250012, China.Department of Rheumatology, Shandong University Qilu Hospital, Jinan, 250012, China.Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China. zli@sdu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28210955

Citation

Zhang, Lei, et al. "The Effects of IGF-1 On TNF-α-Treated DRG Neurons By Modulating ATF3 and GAP-43 Expression Via PI3K/Akt/S6K Signaling Pathway." Neurochemical Research, vol. 42, no. 5, 2017, pp. 1403-1421.
Zhang L, Yue Y, Ouyang M, et al. The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway. Neurochem Res. 2017;42(5):1403-1421.
Zhang, L., Yue, Y., Ouyang, M., Liu, H., & Li, Z. (2017). The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway. Neurochemical Research, 42(5), 1403-1421. https://doi.org/10.1007/s11064-017-2192-1
Zhang L, et al. The Effects of IGF-1 On TNF-α-Treated DRG Neurons By Modulating ATF3 and GAP-43 Expression Via PI3K/Akt/S6K Signaling Pathway. Neurochem Res. 2017;42(5):1403-1421. PubMed PMID: 28210955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway. AU - Zhang,Lei, AU - Yue,Yaping, AU - Ouyang,Meishuo, AU - Liu,Huaxiang, AU - Li,Zhenzhong, Y1 - 2017/02/16/ PY - 2016/09/18/received PY - 2017/01/24/accepted PY - 2017/01/21/revised PY - 2017/2/18/pubmed PY - 2018/1/10/medline PY - 2017/2/18/entrez KW - Activating transcription factor 3 KW - Dorsal root ganglion KW - Growth-associated protein 43 KW - Insulin-like growth factor-1 KW - Neurite outgrowth KW - Neuron KW - Tumor necrosis factor-α SP - 1403 EP - 1421 JF - Neurochemical research JO - Neurochem. Res. VL - 42 IS - 5 N2 - 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. SN - 1573-6903 UR - https://www.unboundmedicine.com/medline/citation/28210955/The_Effects_of_IGF_1_on_TNF_α_Treated_DRG_Neurons_by_Modulating_ATF3_and_GAP_43_Expression_via_PI3K/Akt/S6K_Signaling_Pathway_ L2 - https://doi.org/10.1007/s11064-017-2192-1 DB - PRIME DP - Unbound Medicine ER -