title: High mobility group box-1 protein regulate immunosuppression of regulatory T cells through toll-like receptor 4.
abstract: BACKGROUND
  High mobility group box-1 protein (HMGB1), a recently recognized mediator of immune response might contribute to immune suppression when released extracellularly. The present study was performed to clarify effects of HMGB1 on regulatory T cells (Tregs) and the involvement of toll-like receptor (TLR) 4 signaling.
  
  
  METHODS
  CD4(+)CD25(+)Tregs, isolated from spleens of normal mice and treated with HMGB1 in vitro, and those isolated from HMGB1-treated C3H/HeN (wild type) or C3H/HeJ (TLR4 mutant type) mice, were analyzed for expressions of cytotoxic T lymphocyte-associated antigen (CTLA)4, forkhead/winged helix transcription factor p3 (Foxp3) and interleukin (IL)-10 secretion.
  
  
  RESULTS
  HMGB1-treatment was found to markedly decrease the expressions of CTLA4 and Foxp3, as well as IL-10 secretion. Administration of TLR4 neutralizing antibody abolished the phenotypic and functional changes in Tregs induced by HMGB1. Tregs from HMGB1-treated normal mice showed lower expression of CTLA4, Foxp3, and IL-10 secretion when compared with non-treated mice. Yet opposite results were observed in that of C3H/HeJ mice. Moreover, HMGB1 stimulation could down-regulate the expression of TLR4 on Tregs.
  
  
  CONCLUSIONS
  Our data suggest that HMGB1 has the ability to directly modulate the suppressive capacity of CD4(+)CD25(+)Tregs, and TLR4 might be a potential receptor essential for the negative effect of HMGB1 on CD4(+)CD25(+)Tregs activity.
authors.affiliation: Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, People's Republic of China. xiaomeizhul@163.com
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Zhu
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yao
authors.forename: Hua-Ping
authors.initials: HP
authors.lastname: Liang
authors.forename: Chang-Tao
authors.initials: CT
authors.lastname: Xu
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 / Q000378:metabolism; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D024243:HMGB1 Protein; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D051197:Toll-Like Receptor 4; D016753:Interleukin-10