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Cell Signal ; 25(6): 1348-60, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23499905

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.


Subject(s)
Extracellular Signal-Regulated MAP Kinases/metabolism , Interleukin-6/metabolism , Janus Kinase 2/metabolism , Receptor, Muscarinic M1/metabolism , STAT3 Transcription Factor/metabolism , Trimethyltin Compounds/toxicity , Animals , Cognition Disorders/chemically induced , Cognition Disorders/metabolism , Cognition Disorders/pathology , Dicyclomine/pharmacology , Hippocampus/metabolism , Interferon-gamma/deficiency , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-6/deficiency , Interleukin-6/genetics , Janus Kinase 2/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation/drug effects , Receptor, Muscarinic M1/antagonists & inhibitors , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Recombinant Proteins/pharmacology , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Tyrphostins/pharmacology
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