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

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22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1348-1360
Number of pages13
JournalCellular Signalling
Volume25
Issue number6
DOIs
Publication statusPublished - 2013 Jun 1

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Keywords

  • Cognitive impairments
  • Extracellular signal-regulated kinase
  • Hippocampus
  • Interlukin-6 gene
  • M1 muscarinic acetylcholine receptor

ASJC Scopus subject areas

  • Cell Biology

Cite this

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