Open AccessA Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages
Author(s) -
ChiehShan Wu,
WenLi Hsu,
Chun-Hsiung Wang,
JuiLin Liang,
MingHsien Tsai,
ChiaJung Yen,
Hsiu-Wen Li,
Siou-Jin Chiu,
Chia-Wen Chang,
YawBin Huang,
MingWei Lin,
Tohru Yoshioka
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0159299
Subject(s) - downregulation and upregulation , tumor necrosis factor alpha , scrub typhus , hsp70 , cytokine , chemistry , biology , microbiology and biotechnology , immunology , heat shock protein , virology , biochemistry , gene
Orientia ( O .) tsutsugamushi -induced scrub typhus is endemic across many regions of Asia and the Western Pacific, where an estimated 1 million cases occur each year; the majority of patients infected with O . tsutsugamushi end up with a cytokine storm from a severe inflammatory response. Previous reports have indicated that blocking tumor necrosis factor (TNF)-α reduced cell injury from a cytokine storm. Since TNF-α production is known to be associated with intracellular Ca 2+ elevation, we examined the effect of store-operated Ca 2+ entry (SOCE) inhibitors on TNF-α production in O . tsutsugamushi -infected macrophages. We found that 2-aminoethoxydiphenyl borate (2-APB), but not SKF96365, facilitates the suppression of Ca 2+ mobilization via the interruption of Orai1 expression in O . tsutsugamushi -infected macrophages. Due to the decrease of Ca 2+ elevation, the expression of TNF-α and its release from macrophages was repressed by 2-APB. In addition, a novel role of 2-APB was found in macrophages that causes the upregulation of heat shock protein 70 (HSP70) expression associated with ERK activation; upregulated TNF-α production in the case of knockdown HSP70 was inhibited with 2-APB treatment. Furthermore, elevated HSP70 formation unexpectedly did not help the cell survival of O . tsutsugamushi -infected macrophages. In conclusion, the parallelism between downregulated Ca 2+ mobilization via SOCE and upregulated HSP70 after treatment with 2-APB against TNF-α production was found to efficiently attenuate an O . tsutsugamushi -induced severe inflammatory response.