Guanabenz Downregulates Inflammatory Responses via eIF2? Dependent and Independent Signaling.

ABSTRACT: Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 ? (eIF2?)-mediated signaling. Alleviating ISR by modulating eIF2? phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2? 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 eIF2? by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2?. Although expression of IL1? and Tumor Necrosis Factor-? (TNF?) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2? signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2?-dependent but also eIF2?-independent signaling.

SUBMITTER: Takigawa S 

PROVIDER: S-EPMC4881500 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature