title: A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages.
abstract: 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.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Dermatology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.|The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Chun-Hsiung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Chi Mei Medical Center, Liouying, Tainan, Taiwan.
authors.forename: Jui-Lin
authors.initials: JL
authors.lastname: Liang
authors.affiliation: Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hsiu-Wen
authors.initials: HW
authors.lastname: Li
authors.affiliation: Institute of Physics, Academia Sinica, Taipei, Taiwan.
authors.forename: Siou-Jin
authors.initials: SJ
authors.lastname: Chiu
authors.affiliation: Department of Dermatology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Chang
authors.affiliation: School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yaw-Bin
authors.initials: YB
authors.lastname: Huang
authors.affiliation: Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yoshioka
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D052139:Intracellular Calcium-Sensing Proteins; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D012285:Orientia tsutsugamushi / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D001896:Boron Compounds; D018840:HSP70 Heat-Shock Proteins; D007093:Imidazoles; D052139:Intracellular Calcium-Sensing Proteins; D008565:Membrane Proteins; C572578:SARAF protein, human; D014409:Tumor Necrosis Factor-alpha; C109986:2-aminoethoxydiphenyl borate; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole