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Reducing Effect of IL-32α in the Development of Stroke Through Blocking of NF-κB, but Enhancement of STAT3 Pathways

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Abstract

Neuroinflammation is important for the development of several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and stroke. Since changes of cytokine level are critical for neuroinflammation in the brain, we investigated whether IL-32α overexpression could change neuroinflammation and, thus, affect stroke development. Middle cerebral artery occlusion (MCAO) induced development of ischemia, and ischemic neuronal cell death were reduced in IL-32α-overexpressing transgenic mice (IL-32α mice) brain through the decreased release of neuroinflammatory cytokines (IL-6, IL-1β, TNF-α) and activation of astrocytes, but enhancement of anti-neuroinflammatory cytokines (IL-10). Reactive oxygen species generation and lipid peroxidation as well as expression of inducible nitric oxide and cyclooxygenase-2 were also reduced in the IL-32α mice brain. Nuclear factor-kappa B (NF-κB), a critical transcriptional factor regulating neuroinflammation, was much lower, but activation of signal transducer and activator of transcription 3 (STAT3), which plays a crucial role in cell survival and proliferation, was much higher in IL-32α-overexpressing mice brain compared to those of wild-type mice brain. These results suggest that IL-32α can prevent cerebral ischemia damage via upregulation of anti-neuroinflammatory cytokine expression and STAT3 activation, but downregulation of neuroinflammatory cytokines and NF-κB activation.

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Abbreviations

ANOVA:

Analysis of variance

COX-2:

Cyclooxygenase-2

DCM:

Dichloromethane

ELISA:

Enzyme-linked immunosorbent assay

EMSA:

Gel electromobility shift assay

GFAP:

Glial fibrillary acidic protein

IL:

Interleukin

IκB:

Inhibitor of κB

iNOS:

Inducible nitric oxide synthase

KO:

Knockout

MCAO:

Middle cerebral artery occlusion

NF-κB:

Nuclear factor-kappa B

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

STAT:

Signal transducer and activator of transcription

TNF:

Tumor necrosis factor

TTC:

2,3,5-Triphenyltetrazolium chloride.

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Acknowledgments

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean Government (MSIP; MRC, 2008–0062275), by a grant (A101836) from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea.

Conflict of Interests

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. College of Pharmacy and Medical Research Center, Chungbuk National University, 12 Gaeshin, Heungduk, Cheongju, Chungbuk, 361-763, Republic of Korea

    Chul Ju Hwang, Hyung-Mun Yun, Yu Yeon Jung, Dong Hun Lee, Hyun Ok Seo, Jin-Yi Han, Ki-Wan Oh, Sang-Bae Han & Jin Tae Hong

  2. Osong Health Technology Administration Complex, 187 Osongsaengmyeong2 (i)-ro, Osong-eup, Cheongwon-gun, Chungbuk, 363-700, Republic of Korea

    Na Young Yoon

  3. College of Pharmacy, Young Nam University, Dae, Gyeongsan, Gyeongbuk, 712-749, Republic of Korea

    Dong Young Choi

  4. Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Republic of Korea

    Do Young Yoon

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  1. Chul Ju Hwang
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Correspondence to Do Young Yoon or Jin Tae Hong.

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Supplementary Fig 1

Possible pathway. IL-32α reduce neuronal cell death as well as brain infarction through down regulate activation of NF-κB but up regulate activation of STAT3. (GIF 24 kb)

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Hwang, C.J., Yun, HM., Jung, Y.Y. et al. Reducing Effect of IL-32α in the Development of Stroke Through Blocking of NF-κB, but Enhancement of STAT3 Pathways. Mol Neurobiol 51, 648–660 (2015). https://doi.org/10.1007/s12035-014-8739-0

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