title: Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. wonderfulmexicancombo@hotmail.com.|Department of Orthopadic Surgery, Mie University Graduate School of Medicine, Mie 514-8507, Japan. wonderfulmexicancombo@hotmail.com.
authors.forename: Shinya
authors.initials: S
authors.lastname: Takigawa
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 40907, USA. andychen@iupui.edu.
authors.forename: Andy
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. meiten0903@gmail.com.|Department of Orthopadic Surgery, Mie University Graduate School of Medicine, Mie 514-8507, Japan. meiten0903@gmail.com.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. liu441@iupui.edu.|Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China. liu441@iupui.edu.
authors.forename: Shengzhi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China. liby@ems.hrbmu.edu.cn.
authors.forename: Bai-Yan
authors.initials: BY
authors.lastname: Li
authors.affiliation: Department of Orthopadic Surgery, Mie University Graduate School of Medicine, Mie 514-8507, Japan. a-sudou@clin.medic.mie-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sudo
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. hyokota@iupui.edu.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. hamak@dpc.agu.ac.jp.|Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan. hamak@dpc.agu.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hamamura
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006143:Guanabenz / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015852:Eukaryotic Initiation Factor-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051546:Cyclooxygenase 2; D006143:Guanabenz
keywords: Csf2 (GM-CSF); eIF2α signaling; guanabenz; inflammation; microarray