title: Murine tumor necrosis factor α-induced adipose-related protein (tumor necrosis factor α-induced protein 9) deficiency leads to arthritis via interleukin-6 overproduction with enhanced NF-κB, STAT-3 signaling, and dysregulated apoptosis of macrophages.
abstract: OBJECTIVE
  To elucidate the role of tumor necrosis factor α-induced adipose-related protein (TIARP; or tumor necrosis factor α-induced protein 9 [TNFAIP-9]) in the development and pathogenesis of arthritis.
  
  
  METHODS
  We generated TIARP-deficient (TIARP(-/-) ) mice and investigated several organs in aged mice. Peritoneal macrophages were collected and cultured with lipopolysaccharide (LPS) and TNFα, and then the production of cytokines and subsequent NF-κB signal transduction were analyzed. We also examined the susceptibility of young TIARP(-/-)  mice to collagen-induced arthritis (CIA). Draining lymph nodes and splenocytes were isolated and cultured, and serum levels of anti-type II collagen (anti-CII) antibodies, interleukin-6 (IL-6), and TNFα on day 60 were measured. We further investigated the effects of anti-IL-6 receptor monoclonal antibody (mAb) on the development of arthritis in TIARP(-/-)  mice. IL-6/STAT-3 signaling was also analyzed using TIARP(-/-)  macrophages.
  
  
  RESULTS
  TIARP(-/-)  mice developed spontaneous enthesitis and synovitis, had high serum levels of IL-6, had increased CD11b+ cell counts in the spleen, and showed enhanced LPS- and TNFα-induced IL-6 expression in macrophages. Sustained degradation of IκBα with dysregulated apoptosis was also noted in TIARP(-/-)  macrophages. CIA was clearly exacerbated in TIARP(-/-)  mice, accompanied by marked neutrophil and macrophage infiltration in joints. The levels of anti-CII antibodies in serum were unchanged, whereas autoreactive Th1 cell and Th17 cell responses were higher in TIARP(-/-)  mice. Treatment with anti-IL-6 receptor mAb prevented the development of CIA in TIARP(-/-)  mice, and TIARP(-/-)  macrophages showed increased IL-6-induced STAT-3 phosphorylation.
  
  
  CONCLUSIONS
  These findings suggest that TIARP acts as a negative regulator of arthritis by suppressing IL-6 production, its signaling and TNFα-induced NF-κB signaling, resulting in enhanced apoptosis in macrophages.
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Naoto
authors.initials: N
authors.lastname: Umeda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001168:Arthritis / Q000378:metabolism* / Q000473:pathology; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000473:pathology; D058504:Th17 Cells / Q000473:pathology
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C436323:Tiarp protein, mouse