title: Ionizing Radiation Induces Innate Immune Responses in Macrophages by Generation of Mitochondrial Reactive Oxygen Species.
abstract: During radiotherapy for tumors, the innate immune system also responds to ionizing radiation and induces immune modulation. However, little is known about the molecular mechanisms by which radiation modulates innate immune responses. In this study, we observed that radiation triggered the generation of mitochondrial reactive oxygen species (mROS), leading to innate immune responses in murine bone marrow-derived macrophages (BMDM). Radiation-induced mROS was essential for robust induction of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-12p40 mRNA and protein in BMDM. Exposure to radiation also led to rapid activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB pathways in BMDM. Notably, radiation-induced MAPK activation and NF-κB signaling were regulated by mROS in macrophages. Additionally, radiation-induced expression of TNF-α, IL-6 and IL-12p40 was dependent on JNK, p38 and NF-κB activation in BMDM. These data suggest a key role for radiation-induced pro-inflammatory responses and activation of the MAPK and NF-κB pathways through a triggering mechanism involving mROS generation.
authors.affiliation: Department of aRadiation Oncology, Daejeon, Korea.|b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Sup
authors.initials: S
authors.lastname: Kim
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Choe
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Gippeum Joy
authors.initials: GJ
authors.lastname: Lee
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Yi Sak
authors.initials: YS
authors.lastname: Kim
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Jin
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
authors.affiliation: d   Department of Pathology, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of aRadiation Oncology, Daejeon, Korea.
authors.forename: Moon-June
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: e   Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.affiliation: b   Department of Medical Science, Daejeon, Korea.|c   Department of Infection Signaling Network Research Center, Daejeon, Korea.
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
authors.affiliation: Department of aRadiation Oncology, Daejeon, Korea.
authors.forename: Jun-Sang
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D004789:Enzyme Activation / Q000528:radiation effects; D005260:Female; D005786:Gene Expression Regulation / Q000528:radiation effects; D053583:Interleukin-1beta / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases