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

doi: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

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 language	English
Pages (from-to)	1348-1360
Number of pages	13
Journal	Cellular Signalling
Volume	25
Issue number	6
DOIs	https://doi.org/10.1016/j.cellsig.2013.02.017
Publication status	Published - 06-2013
Externally published	Yes

All Science Journal Classification (ASJC) codes

Cell Biology

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10.1016/j.cellsig.2013.02.017

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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

@article{ad1313da0d1c4704af1e7be025d8b4a6,

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

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}",

note = "Funding Information: This study was supported by a grant from the Brain Research Center from the 21st Century Frontier Research Program ( 2012k001115 ) funded by the Ministry of Science and Technology, Republic of Korea . This work was, in part, supported by a grant from the Bio & Medical Technology Development Program ( 20120006020 ) through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea , and by grants from Ministry of Health Labour and Welfare (MHLW) : Research on Risk of Chemical Substances, and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project. Jae-Hyung Bach was supported by the BK 21 program. ",

year = "2013",

month = jun,

doi = "10.1016/j.cellsig.2013.02.017",

language = "English",

volume = "25",

pages = "1348--1360",

journal = "Cellular Signalling",

issn = "0898-6568",

publisher = "Elsevier Inc.",

number = "6",

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TY - JOUR

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

N1 - Funding Information: This study was supported by a grant from the Brain Research Center from the 21st Century Frontier Research Program ( 2012k001115 ) funded by the Ministry of Science and Technology, Republic of Korea . This work was, in part, supported by a grant from the Bio & Medical Technology Development Program ( 20120006020 ) through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea , and by grants from Ministry of Health Labour and Welfare (MHLW) : Research on Risk of Chemical Substances, and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project. Jae-Hyung Bach was supported by the BK 21 program.

PY - 2013/6

Y1 - 2013/6

N2 - 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.

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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VL - 25

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JO - Cellular Signalling

JF - Cellular Signalling

IS - 6

ER -

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

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