Up-regulation of activating transcription factor-5 suppresses SAP expression to activate T cells in hemophagocytic syndrome associated with Epstein-Barr virus infection and immune disorders

Huai Chia Chuang, Ju Ming Wang, Wen Chuan Hsieh, Yao Chang, Ih Jen Su

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Hemophagocytic syndrome (HPS) is a fatal, pro-inflammatory cytokine disorder that is associated with viral infections and immune disorders. Previously, we demonstrated that Epstein-Barr virus latent membrane protein-1 (LMP-1) could down-regulate the SAP gene, enhancing Th1 cytokine secretion in T cells and leading to HPS. The exact mechanism of SAP gene regulation by LMP-1 remains to be clarified. In this study, using cDNA microarray analysis, we identified ATF5 as the candidate transcriptional repressor for SAP expression in LMP-1-expressing T cells. LMP-1 up-regulated ATF5 via TRAF2,5/NF-κB signals to suppress SAP gene expression. Reporter assays and electrophoretic mobility shift assays revealed that ATF5 bound differentially to two sites of the SAP promoter. In resting T cells, ATF5 bound predominantly to the high-affinity site in the -81 to -74 region while additionally binding to the low-affinity site at -305 to -296 in LMP-1-expressing T cells. Such binding subsequently disrupted the transcription of the SAP gene. At the same time, Th1 cytokine secretion was enhanced. This phenomenon was also observed in conditions such as ATF5 overexpression, phytohemagglutinin stimulation of primary T cells, and ligand engagement of T-cell lines. Therefore, the down-regulation of the SAP gene by ATF5 may represent a common mechanism for the pathogenesis of HPS that is associated with either Epstein-Barr virus infection or immune disorders with dysregulated T-cell activation.

Original languageEnglish
Pages (from-to)1397-1405
Number of pages9
JournalAmerican Journal of Pathology
Volume173
Issue number5
DOIs
Publication statusPublished - 2008 Nov

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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