title: Cross-Regulation of Proinflammatory Cytokines by Interleukin-10 and miR-155 in Orientia tsutsugamushi-Infected Human Macrophages Prevents Cytokine Storm.
abstract: Scrub typhus is caused by the obligate intracellular bacterium Orientia tsutsugamushi. Macrophages are host cells for its replication and clearance. Severe complications in patients are mainly caused by a cytokine storm resulting from overproduction of proinflammatory cytokines; nevertheless, the molecular mechanism for the occurrence remains obscure. Herein, we investigate the interactive regulation of cytokines and micro-RNA (miR) in human macrophages infected with low and high doses of O. tsutsugamushi. During low dose infection, macrophages produce high levels of IL-10 through extracellular signal-regulated kinase activation, which inhibits proinflammatory cytokine production and facilitates pathogen replication. Increasing levels of pathogen results in reduced levels of IL-10, and macrophages begin to generate high levels of proinflammatory cytokines through NF-κB activation. However, during a high dose infection, macrophages produce high levels of miR-155 to slow the proinflammatory response. The extracellular signal-regulated kinase/IL-10 axis suppresses the NF-κB/tumor necrosis factor alpha axis via activation of signal transducer and activator of transcription 3. Both IL-10 and miR-155 inhibit the NF-κB signaling pathway. Furthermore, IL-10 is a potent inhibitor of miR-155. Patients susceptible to a cytokine storm, peripheral blood mononuclear cells showed significantly lower IL-10 and miR-155 responses to O. tsutsugamushi challenge. Thus, IL-10 and miR-155 operate inhibitory mechanisms to achieve a proper defense mechanism and prevent a cytokine storm.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Research Center for Applied Sciences, Academic Sinica, Taipei, Taiwan. Electronic address: 970457@ms.kmuh.org.tw.
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Institute of Medical Sciences, School of Medicine, Tzu Chi University, Hualien, Taiwan; Institute of Eye Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. Electronic address: tasi.rk@gmail.com.
authors.forename: Rong-Kung
authors.initials: RK
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Hong
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
authors.affiliation: Department of Dermatology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Kan-Tang
authors.initials: KT
authors.lastname: Fan
authors.affiliation: Institute of Medical Sciences, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chi-Wen
authors.initials: CW
authors.lastname: Peng
authors.affiliation: Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Lih-Shinn
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Medical Laboratory, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Li-Kuang
authors.initials: LK
authors.lastname: Chen
authors.affiliation: Research Center for Applied Sciences, Academic Sinica, Taipei, Taiwan; National Environmental Health Research Center, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Hsin-Su
authors.initials: HS
authors.lastname: Yu
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012285:Orientia tsutsugamushi; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012612:Scrub Typhus / Q000276:immunology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases