title: Dendritic cells contribute to autoimmune kidney injury in MRL-Faslpr mice.
abstract: OBJECTIVE
  Dendritic cells (DC) contribute to autoimmune disease progression and pathogenesis. Mature DC have been reported to secrete high mobility group box protein (HMGB-1), a novel inflammatory cytokine, via p38 mitogen-activated protein kinase (MAPK) activation. We investigated whether DC are involved in progression of autoimmune diseases followed by secretion of HMGB-1 via p38 MAPK activation in a lupus-prone mouse model.
  
  
  METHODS
  FR167653, a specific inhibitor of p38 MAPK, was given orally from 3 months of age in MRL-Fas(lpr) mice. Cultured DC, treated with or without FR167653, were stimulated with tumor necrosis factor-alpha.
  
  
  RESULTS
  Inhibition of p38 MAPK led to a reduction in the number of CD11c-positive cells, including those with the mature phenotype, in the diseased kidney and spleen, which resulted in improvement of kidney pathology in MRL-Fas(lpr) mice. The number of CD11c-positive cells in circulation was also reduced. HMGB-1 protein and transcripts detected in the diseased kidney, and the number of cells dual-positive for HMGB-1 and CD11c, were reduced by inhibition of p38 MAPK. Maturation of cultured DC and increased cytokines, including HMGB-1, in the supernatant were inhibited by FR167653 treatment. These results suggest that DC are involved in the progression of autoimmune kidney diseases in MRL-Fas(lpr) mice followed by HMGB-1 secretion via p38 MAPK activation.
  
  
  CONCLUSIONS
  Our results indicated that DC secrete HMGB-1 via p38 MAPK activation to participate in autoimmunity in MRL-Fas(lpr) mice.
authors.affiliation: Department of Disease Control, Institute of Medical, Pharmaceutical and Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iwata
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kurokawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Toyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Kitajima
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okumura
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D039521:CD11c Antigen / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; D004791:Enzyme Inhibitors; C104334:FR 167653; D024243:HMGB1 Protein; D011720:Pyrazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases