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

doi:10.1016/j.cellsig.2013.02.017

Cellular Signalling

Volume 25, Issue 6, June 2013, Pages 1348-1360

https://doi.org/10.1016/j.cellsig.2013.02.017 Get rights and content

Highlights

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TMT inhibited JAK2/STAT3 axis, ChAT, and M1 mAChR expressions in the hippocampus.
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IL-6 gene deficiency potentiated TMT-induced cognitive dysfunction.
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rIL-6 attenuated the inhibition of JAK2/STAT3 axis in TMT-treated IL-6^–/– mice.
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rIL-6 restored M1 mAChR-ERK signaling and memory function in TMT-treated IL-6^–/– mice.
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IL-6 gene is essential for recovering cholinergic function after TMT-induced toxicity.

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.

Graphical abstract

Introduction

Trimethyltin (TMT) intoxication results in behavioral modifications such as increased seizure susceptibility, hyperactivity, aggression, and learning impairment [1], [2], [3], [4], [5] and is thus regarded as a suitable model of chronic neurodegeneration with cognitive impairment [2], [4]. TMT-induced cognitive impairment may be useful in the study of Alzheimer's disease (AD) [6], [7], [8], [9]. Indeed, it has been shown that blood tin levels elevate in patients with AD [6], [7], and that TMT produces a syndrome with similarities to that of AD [9], [10].

Increasing evidence suggests that cytokines participate not only in functions related to the immune system but also in complex functions of the central nervous system, such as cognition [11]. For example, cytokines have been reported to affect cognitive function during infection [12], in neurodegenerative diseases [11], and in neuropsychiatric disorders [13]. Interleukin (IL)-6, in particular, is reported to modulate cognitive function [14], [15] and to play a mechanistic role in the pathogenesis of AD, although the mechanism mediating this effect remains to be determined [16]. It is known that IL-6 potentiates the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis by activating STAT3 (Nakashima and Taga, 2002). Chiba et al. [17] proposed a novel theory accounting for memory dysfunction in AD, whereby amyloid β-dependent inactivation of the JAK2/STAT3 axis in hippocampal neurons may cause memory impairment related to AD. Recently, we demonstrated that IL-6 protects against TMT-induced excitotoxic seizures via a Nrf-2-dependent glutathione (GSH) defense mechanism and phosphoinositide 3-kinase (PI3K)/Akt-dependent signaling [18]. In the present study, we examined the role of IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in TMT-induced memory impairment to investigate the molecular mechanism by which cytokines affect cognition. We observed that IL-6 knockout mice (IL-6^−/−) were the most susceptible to TMT-induced memory impairment. We observed that central administration of IL-6 receptor neutralizing antibody (IL-6R Ab) in wild-type (WT) animals potentiated TMT-induced memory impairment, whereas recombinant IL-6 protein (rIL-6) significantly inhibited memory impairments induced by TMT in IL-6^−/− mice. Furthermore, we found that rIL-6 attenuated inactivated JAK2/STAT3 signaling and down-regulated the M1 muscarinic acetylcholine receptor (mAChR), resulting in enhanced extracellular signal-regulated protein kinase (ERK) phosphorylation and memory improvement. This suggests that IL-6 has an essential role in improving memory function by activating JAK2/STAT3 signaling and upregulating the M1 mAChR.

Section snippets

Animals

We used IL-6^−/−, TNFα^−/−, and INF-γ^−/− mice of the C57BL/6 background strain as previously reported [18], [19], [20], [21]. Breeding pairs were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Mice were bred and housed in an approved animal facility at Kangwon National University. We purchased C57BL/6 of wild-type (WT) animals from Orient Bio Inc. (Charles River Technology, Seoul, Korea). All mice were treated in accordance with the NIH Guide for the Humane Care and Use of

Trimethyltin (TMT)-induced memory impairments in IL-6 knockout mice

In this study, we examined the role of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in cognitive impairments induced by TMT using knockout mice (^−/−). TMT-induced memory impairments were evaluated by Y-maze task (Fig. 1A) and passive avoidance test (Fig. 1B). ANOVA indicated a significant main effects of TMT on the performances in the Y-maze task (P = 5.74 × 10^− 8) and passive avoidance test (P = 3.11 × 10^− 8). Post-hoc test revealed that there was no difference in

Discussion

The results of this study demonstrate that IL-6 gene deficiency in IL-6^−/− mice selectively potentiates TMT-induced memory impairment by decreasing M1 mAChR gene expression, ACh level, ChAT activity, and ChAT gene expression and by increasing AChE activity and AChE gene expression. Impairments in the cholinergic system may be due to IL-6 deficiency in presynaptic cholinergic nerve terminals and postsynaptic neurons expressing M1 mAChR in the hippocampus. Furthermore, we found that IL-6

Acknowledgments

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):

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Therefore, it is possible that the effects produced by AG490 (or the lack thereof) could be due to off-target effects of the drug. Although this is a limitation, it is a minor one given previous studies that demonstrated its ability to effectively block IL-6 signaling effects in the brain on STAT3 phosphorylation, and also on behavioral processes known to be affected by IL-6 (Damm et al., 2013; Kim et al., 2013). Another possible explanation for the lack of AG490 effects in the CTA compared to the LORR study is that there was no 30-min incubation time between the AG490 administration and the ethanol.
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¹: First two authors (BKK and HYPT) contributed equally to this work.

²: Present address: University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam.

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

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Animals

Trimethyltin (TMT)-induced memory impairments in IL-6 knockout mice

Discussion

Acknowledgments

Neuroscience

Neuroscience

Neurochemistry International

Neurochemistry International

Prostaglandins, Leukotrienes, and Essential Fatty Acids

Molecular Brain Research

Neuroscience and Biobehavioral Reviews

Trends in Immunology

Behavioural Brain Research

European Journal of Pharmacology

Brain Research Reviews

Free Radical Biology & Medicine

Biochimica et Biophysica Acta

Journal of Pharmacological Sciences

Pharmacological Research

Behavioural Brain Research

Analytical Biochemistry

Molecular and Cellular Neuroscience

Molecular Brain Research

Neurobiology of Aging

Trends in Neurosciences

Current Opinion in Neurobiology

Neurobehavioral Toxicology and Teratology

Human and Experimental Toxicology