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

Research output: Contribution to journalArticle

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

Fingerprint

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

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

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

Kim, BK, Tran, HYP, Shin, EJ, Lee, C, Chung, YH, Jeong, JH, Bach, JH, Kim, W-K, 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
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.
@article{6ad089363abe44969aee674e52a4f959,
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.",
keywords = "Cognitive impairments, Extracellular signal-regulated kinase, Hippocampus, Interlukin-6 gene, M1 muscarinic acetylcholine receptor",
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 Won-Ki Kim and Park, {Dae Hoon} and Kuniaki Saito and Toshitaka Nabeshima and Kim, {Hyoung Chun}",
year = "2013",
month = "6",
day = "1",
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",

}

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

PY - 2013/6/1

Y1 - 2013/6/1

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.

KW - Cognitive impairments

KW - Extracellular signal-regulated kinase

KW - Hippocampus

KW - Interlukin-6 gene

KW - M1 muscarinic acetylcholine receptor

UR - http://www.scopus.com/inward/record.url?scp=84876323219&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876323219&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2013.02.017

DO - 10.1016/j.cellsig.2013.02.017

M3 - Article

C2 - 23499905

AN - SCOPUS:84876323219

VL - 25

SP - 1348

EP - 1360

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 6

ER -