Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling

International Journal of Molecular Sciences

Kazunori Hamamura¹  Shengzhi Liu¹  Shinya Takigawa¹  Hiroki Yokota¹  Akinobu Nishimura¹  Akihiro Sudo²  Bai-Yan Li³  Andy Chen⁴ 

[1] 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;Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China;Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 40907, USA;

关键词: guanabenz;    microarray;    inflammation;    Csf2 (GM-CSF);    eIF2α signaling;   

DOI  :  10.3390/ijms17050674

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown