title: TLR4-mediated IL-12 production enhances IFN-γ and IL-1β production, which inhibits TGF-β production and promotes antibody-induced joint inflammation.
abstract: BACKGROUND
  Toll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1β in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis.
  
  
  METHODS
  To induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration.
  
  
  RESULTS
  Compared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-γ, IL-12p35 and IL-1β transcript levels in the joints, but high transforming growth factor (TGF)-β expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-γ and IL-1β production via T-bet and pro-IL-1β production. Recombinant IL-12, IFN-γ and IL-1β administration restored arthritis, but reduced joint TGF-β levels in TLR4-/- mice. Moreover, a TGF-β blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4-/- mice.
  
  
  CONCLUSIONS
  TLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-γ and IL-1β production, which suppresses TGF-β production, thereby promoting antibody-induced arthritis.
authors.forename: Hye Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma