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Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2016 May 05; Vol. 17 (5). Date of Electronic Publication: 2016 May 05. - Publication Year :
- 2016
-
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.
- Subjects :
- Animals
Bone Marrow Cells drug effects
Bone Marrow Cells metabolism
Cells, Cultured
Cyclooxygenase 2 metabolism
Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Humans
Inflammation metabolism
Interleukin-6 metabolism
Jurkat Cells
Macrophages drug effects
Macrophages metabolism
Mast Cells drug effects
Mast Cells metabolism
Mice
Transcriptome
Tumor Necrosis Factor-alpha metabolism
Anti-Inflammatory Agents pharmacology
Down-Regulation
Eukaryotic Initiation Factor-2 metabolism
Guanabenz pharmacology
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 17
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 27164082
- Full Text :
- https://doi.org/10.3390/ijms17050674