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IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo¹

Keun W. Park^*,, Hyung H. Baik^*, and Byung K. Jin^2,*,,,

^* Department of Biochemistry & Molecular biology, Brain Korea 21 Project Center, Neurodegeneration Control Research Center, Age-related & Brain Diseases Research Center, School of Medicine Kyung Hee University, Seoul, South Korea

In the present study, we investigated the effects of IL-13, a well-known anti-inflammatory cytokine, on the thrombin-treated hippocampus in vivo. NeuN immunohistochemistry and Nissl staining revealed significant loss of hippocampal CA1 neurons upon intrahippocampal injection of thrombin. This neurotoxicity was accompanied by substantial microglial activation, as evident from OX-42 immunohistochemistry results. In parallel, Western blot analysis and hydroethidine histochemistry disclosed activation of NADPH oxidase, generation of reactive oxygen species, and oxidative damage in the hippocampal CA1 area showing hippocampal neuron degeneration. Interestingly, immunohistochemical and biochemical experiments showed that intrahippocampal injection of thrombin increased IL-13 immunoreactivity and IL-13 levels as early as 8 h after thrombin, reaching a peak at 7 days, which was maintained up to 14 days. Moreover, double-label immunohistochemistry revealed IL-13 immunoreactivity exclusively in activated microglia. IL-13-neutralizing Abs significantly rescued CA1 hippocampal neurons from thrombin neurotoxicity. In parallel, neutralization of IL-13 inhibited activation of NADPH oxidase, reactive oxygen species production, and oxidative damage. Additionally, IL-13 neutralization suppressed the expression of inducible NO synthase and several proinflammatory cytokines. To our knowledge, the present study is the first to show that IL-13 triggers microglial NADPH oxidase-derived oxidative stress, leading to the degeneration of hippocampal neurons in vivo, as occurs in cases of Alzheimer’s disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a KOSEF grant funded by the Korea government (R11–2008-036-01001-0) and partly by the Kyung Hee University Research Fund in 2008 (KHU-20080469).

² Address correspondence and reprint requests to Dr. Byung K. Jin, Department of Biochemistry & Molecular Biology, Neurodegeneration Control Research Center, Age-related and Brain Disease Research Center, School of Medicine, Kyung Hee University, Seoul 130–701, South Korea. E-mail address: bkjin{at}khu.ac.kr

³ Abbreviations used in this paper: AD, Alzheimer’s disease; Aβ, β-amyloid; NeuN-ip, NeuN immunopositive; NA, neutralizing Ab; PB, phosphate buffer; DNPH, 2,4-dinitrophenylhydrazine; iNOS, inducible NO synthase.

⁴ The online version of this article contains supplemental material.