IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network

Beom Keun Kim, Haong Yen Phi Tran, Eun Joo Shin, Chaeyoung Lee, Yoon Hee Chung, Ji Hoon Jeong, Jae Hyung Bach, Won Ki Kim, Dae Hoon Park, Kuniaki Saito, Toshitaka Nabeshima, Hyoung Chun Kim

研究成果: Article

22 引用 (Scopus)

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We previously reported that interleukin (IL)-6 deficiency potentiates trimethyltin (TMT)-induced convulsive neurotoxicity. The purpose in this study was to investigate the molecular mechanism by which cytokines affect TMT-induced cognitive impairment. To accomplish this, we examined hippocampal changes in Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in relation to cholinergic parameters after TMT treatment in mice genetically deficient in IL-6 (IL-6-/-), tumor necrosis factor-α (TNF-α-/-), or interferon-γ (IFN-γ-/-). The IL-6-/- mice were the most susceptible to TMT-induced cognitive dysfunction and exhibited significant decreases in JAK2/STAT3 signaling and M1 muscarinic acetylcholine receptor (mAChR) expression, as well as other cholinergic parameters, compared with wild-type (WT) animals. Recombinant IL-6 protein (rIL-6) significantly attenuated these impairments in TMT-treated IL-6-/- mice, whereas an IL-6 receptor antibody potentiated these impairments in TMT-treated WT animals. Inhibition of JAK2 with AG490 or inhibition of cholinergic signaling with the M1 mAChR antagonist dicyclomine counteracted the attenuating effects of rIL-6 on phosphorylated extracellular signal-regulated kinase (ERK) expression, or on cognitive impairment in TMT-treated IL-6-/- mice. However, neither AG490 nor dicyclomine significantly attenuated effects of rIL-6 on acetylcholinesterase values. Our results suggest that activation of JAK2/STAT3 signaling and upregulation of the M1 mAChR are essential components of IL-6-mediated memory improvement against TMT toxicity.

元の言語English
ページ(範囲)1348-1360
ページ数13
ジャーナルCellular Signalling
25
発行部数6
DOI
出版物ステータスPublished - 01-06-2013
外部発表Yes

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Cell Biology

これを引用

Kim, B. K., Tran, H. Y. P., Shin, E. J., Lee, C., Chung, Y. H., Jeong, J. H., Bach, J. H., Kim, W. K., Park, D. H., Saito, K., Nabeshima, T., & Kim, H. C. (2013). IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network. Cellular Signalling, 25(6), 1348-1360. https://doi.org/10.1016/j.cellsig.2013.02.017