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Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling

Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Department of Orthopadic Surgery, Mie University Graduate School of Medicine, Mie 514-8507, Japan
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 40907, USA
Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, 1–100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan
Author to whom correspondence should be addressed.
Academic Editor: Charles J. Malemud
Int. J. Mol. Sci. 2016, 17(5), 674;
Received: 26 March 2016 / Revised: 22 April 2016 / Accepted: 27 April 2016 / Published: 5 May 2016
(This article belongs to the Section Biochemistry)
PDF [2737 KB, uploaded 5 May 2016]


Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages. Genome-wide mRNA profiling followed by principal component analysis predicted that colony stimulating factor 2 (Csf2, or GM-CSF as granulocyte macrophage colony stimulating factor) is involved in the responses to guanabenz. A partial silencing of Csf2 or eIF2α by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2α. Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2α-dependent but also eIF2α-independent signaling. View Full-Text
Keywords: guanabenz; microarray; inflammation; Csf2 (GM-CSF); eIF2α signaling guanabenz; microarray; inflammation; Csf2 (GM-CSF); eIF2α signaling

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Takigawa, S.; Chen, A.; Nishimura, A.; Liu, S.; Li, B.-Y.; Sudo, A.; Yokota, H.; Hamamura, K. Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling. Int. J. Mol. Sci. 2016, 17, 674.

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