A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages.
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 repo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4966960?pdf=render |
| _version_ | 1818187673668419584 |
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| author | Ching-Ying Wu Wen-Li Hsu Chun-Hsiung Wang Jui-Lin Liang Ming-Hsien Tsai Chia-Jung Yen Hsiu-Wen Li Siou-Jin Chiu Chung-Hsing Chang Yaw-Bin Huang Ming-Wei Lin Tohru Yoshioka |
| author_facet | Ching-Ying Wu Wen-Li Hsu Chun-Hsiung Wang Jui-Lin Liang Ming-Hsien Tsai Chia-Jung Yen Hsiu-Wen Li Siou-Jin Chiu Chung-Hsing Chang Yaw-Bin Huang Ming-Wei Lin Tohru Yoshioka |
| author_sort | Ching-Ying Wu |
| collection | DOAJ |
| description | 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 Ca2+ elevation, we examined the effect of store-operated Ca2+ 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 Ca2+ mobilization via the interruption of Orai1 expression in O. tsutsugamushi-infected macrophages. Due to the decrease of Ca2+ 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 Ca2+ 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. |
| first_indexed | 2024-12-11T23:14:46Z |
| format | Article |
| id | doaj.art-406beb159f9c485889c13caa9114cdd4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T23:14:46Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-406beb159f9c485889c13caa9114cdd42022-12-22T00:46:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01117e015929910.1371/journal.pone.0159299A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages.Ching-Ying WuWen-Li HsuChun-Hsiung WangJui-Lin LiangMing-Hsien TsaiChia-Jung YenHsiu-Wen LiSiou-Jin ChiuChung-Hsing ChangYaw-Bin HuangMing-Wei LinTohru YoshiokaOrientia (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 Ca2+ elevation, we examined the effect of store-operated Ca2+ 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 Ca2+ mobilization via the interruption of Orai1 expression in O. tsutsugamushi-infected macrophages. Due to the decrease of Ca2+ 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 Ca2+ 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.http://europepmc.org/articles/PMC4966960?pdf=render |
| spellingShingle | Ching-Ying Wu Wen-Li Hsu Chun-Hsiung Wang Jui-Lin Liang Ming-Hsien Tsai Chia-Jung Yen Hsiu-Wen Li Siou-Jin Chiu Chung-Hsing Chang Yaw-Bin Huang Ming-Wei Lin Tohru Yoshioka A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. PLoS ONE |
| title | A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. |
| title_full | A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. |
| title_fullStr | A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. |
| title_full_unstemmed | A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. |
| title_short | A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages. |
| title_sort | novel strategy for tnf alpha production by 2 apb induced downregulated soce and upregulated hsp70 in o tsutsugamushi infected human macrophages |
| url | http://europepmc.org/articles/PMC4966960?pdf=render |
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