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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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 - 01-06-2013

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Janus Kinase 2
STAT3 Transcription Factor
Extracellular Signal-Regulated MAP Kinases
Muscarinic Receptors
Interleukin-6
Dicyclomine
Cholinergic Agents
Wild Animals
Interleukin-6 Receptors
Proteins
trimethyltin
Cognitive Dysfunction
Cholinergic Antagonists
Acetylcholinesterase
Interferons
Up-Regulation
Tumor Necrosis Factor-alpha
Cytokines
Antibodies

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Kim, Beom Keun ; Tran, Haong Yen Phi ; Shin, Eun Joo ; Lee, Chaeyoung ; Chung, Yoon Hee ; Jeong, Ji Hoon ; Bach, Jae Hyung ; Kim, Won Ki ; Park, Dae Hoon ; Saito, Kuniaki ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network. In: Cellular Signalling. 2013 ; Vol. 25, No. 6. pp. 1348-1360.
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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.",
author = "Kim, {Beom Keun} and Tran, {Haong Yen Phi} and Shin, {Eun Joo} and Chaeyoung Lee and Chung, {Yoon Hee} and Jeong, {Ji Hoon} and Bach, {Jae Hyung} and Kim, {Won Ki} and Park, {Dae Hoon} and Kuniaki Saito and Toshitaka Nabeshima and Kim, {Hyoung Chun}",
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Kim, BK, Tran, HYP, Shin, EJ, Lee, C, Chung, YH, Jeong, JH, Bach, JH, Kim, WK, Park, DH, Saito, K, Nabeshima, T & Kim, HC 2013, 'IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network', Cellular Signalling, vol. 25, no. 6, pp. 1348-1360. https://doi.org/10.1016/j.cellsig.2013.02.017

IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network. / Kim, Beom Keun; Tran, Haong Yen Phi; Shin, Eun Joo; Lee, Chaeyoung; Chung, Yoon Hee; Jeong, Ji Hoon; Bach, Jae Hyung; Kim, Won Ki; Park, Dae Hoon; Saito, Kuniaki; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Cellular Signalling, Vol. 25, No. 6, 01.06.2013, p. 1348-1360.

Research output: Contribution to journalArticle

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T1 - IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network

AU - Kim, Beom Keun

AU - Tran, Haong Yen Phi

AU - Shin, Eun Joo

AU - Lee, Chaeyoung

AU - Chung, Yoon Hee

AU - Jeong, Ji Hoon

AU - Bach, Jae Hyung

AU - Kim, Won Ki

AU - Park, Dae Hoon

AU - Saito, Kuniaki

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

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AB - 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.

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