IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network
- Authors
- Kim, Beom Keun; Haong-Yen Phi Tran; 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
- Issue Date
- 6월-2013
- Publisher
- ELSEVIER SCIENCE INC
- Keywords
- Cognitive impairments; Hippocampus; Intedukin-6 gene; M1 muscarinic acetylcholine receptor; Extracellular signal-regulated kinase
- Citation
- CELLULAR SIGNALLING, v.25, no.6, pp.1348 - 1360
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELLULAR SIGNALLING
- Volume
- 25
- Number
- 6
- Start Page
- 1348
- End Page
- 1360
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/103154
- DOI
- 10.1016/j.cellsig.2013.02.017
- ISSN
- 0898-6568
- 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-alpha (TNE-alpha(-/-)), or interferon-gamma (IFN-gamma(-/-)). 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 phosphotylated 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. (C) 2013 Elsevier Inc. All rights reserved.
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