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.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Beom Keun
authors.initials: BK
authors.lastname: Kim
authors.forename: Haong-Yen Phi
authors.initials: HY
authors.lastname: Tran
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Lee
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Bach
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Dae Hoon
authors.initials: DH
authors.lastname: Park
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004025:Dicyclomine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014298:Trimethyltin Compounds / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D043643:Receptor, Muscarinic M1; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C046488:trimethyltin; D004025:Dicyclomine; D007371:Interferon-gamma; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases