title: Up-regulation of mitofusin-2 protects CD4+ T cells from HMGB1-mediated immune dysfunction partly through Ca(2+)-NFAT signaling pathway.
abstract: High mobility group box 1 protein (HMGB1) was recently discovered to be a critical late-acting cytokine and innate immune-modulating factor in sepsis, but the potential role and mechanism of HMGB1 in adaptive immunity remains elusive. The present study demonstrated that HMGB1 had a dual influence on immune function of CD4(+) T lymphocytes. Low dose of HMGB1 had no effect on the proliferation activity of CD4(+) T lymphocytes, but the Th1 cytokines production was increased. In contrast, treatment with high amount of HMGB1 suppressed the proliferative response and induced Th2 polarization of CD4(+) T lymphocytes. We found that the expression of mitofusin-2 (Mfn2; also named hyperplasia suppressor gene), a member of the mitofusin family, was decreased in CD4(+) T lymphocytes when stimulated with high dose of HMGB1. Up-regulation of Mfn2 attenuated the suppressive effect of HMGB1 on CD4(+) T lymphocytes, which was associated with profound elevation of intracellular calcium concentration ([Ca(2+)](i)) and nuclear factor of activated T cells (NFAT) activity. These results indicate that HMGB1 have a direct role on adaptive immunity, and the decrease of Mfn2 expression may be a major cause of HMGB1-mediated immune dysfunction and Ca(2+)-NFAT signaling defect of CD4(+) T lymphocytes.
authors.affiliation: Emergency Department, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, PR China.
authors.forename: Guang-ju
authors.initials: GJ
authors.lastname: Zhao
authors.forename: Yong-ming
authors.initials: YM
authors.lastname: Yao
authors.forename: Zhong-qiu
authors.initials: ZQ
authors.lastname: Lu
authors.forename: Guang-liang
authors.initials: GL
authors.lastname: Hong
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Zhu
authors.forename: Yao
authors.initials: Y
authors.lastname: Wu
authors.forename: Da-wei
authors.initials: DW
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Dong
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Sheng
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D020013:Calcium Signaling / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects*; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D024243:HMGB1 Protein; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D003208:Concanavalin A; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse