title: Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages.
abstract: BACKGROUND
  The spectrum of TNF-α-producing cells in patients with psoriasis, as well as their fate during treatment with TNF-α antagonists, is not clearly defined.
  
  
  OBJECTIVE
  We sought to analyze the effects of anti-TNF-α treatment on TNF-α(+) cells in the skin and blood of patients with psoriasis.
  
  
  METHODS
  Lesional psoriatic skin was analyzed by means of immunohistologic staining and quantitative RT-PCR, and peripheral blood cells were phenotypically characterized by means of multicolor immunofluorescence labeling.
  
  
  RESULTS
  By using a tyramide-based signal amplification system, TNF-α was detected in dermal CD45(+)HLA-DR(+) leukocytes consisting of CD11c(+) dendritic cells and CD163(+) macrophages. In peripheral blood we observed an increase in the TNF-α-producing myeloid subsets of CD14(-) 6-sulfo-LacNac(+) dendritic cells and CD14(+)CD16(+) "intermediate" monocytes compared with healthy control subjects. Strikingly, we did not find detectable levels of TNF-α in other cells, including keratinocytes or T cells, making these cell types unlikely targets of TNF-α blockers. Up to 48 hours after the intravenous administration of the TNF-α antagonist infliximab, we encountered no overt changes in numbers of TNF-α(+) cells or signs of apoptosis in lesional psoriatic skin. Yet we observed a rapid decrease in IL-12p40, IL-1β, CCL20, and IL12RB1 mRNA levels. Consistently, TNF-α blockade during in vitro stimulation of 6-sulfo-LacNac DCs resulted in decreased production of IL-12 and IL-23 but not IL-6. In a mixed leukocyte reaction infliximab led to significantly decreased proliferation rates of T cells independent of the Fc antibody fragment.
  
  
  CONCLUSIONS
  The decrease in tissue inflammation during anti-TNF-α therapy is not due to immediate killing of TNF-α-producing cells but rather results from a rapid downregulation of the pathogenic IL-12/IL-23-driven immune response.
authors.affiliation: Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Brunner
authors.forename: Frieder
authors.initials: F
authors.lastname: Koszik
authors.forename: Bärbel
authors.initials: B
authors.lastname: Reininger
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Kalb
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bauer
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
mesh_terms: D000328:Adult; D000606:Amino Sugars / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D000069285:Infliximab; D018664:Interleukin-12 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: C467438:6-sulfo-LacNac; D000606:Amino Sugars; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018836:Inflammation Mediators; D053759:Interleukin-23; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000069285:Infliximab
keywords: 6-Sulfo-LacNac; 6-sulfo-LacNac; BDCA; Blood dendritic cell antigen; DC; Dendritic cell; IL-12p40; Inducible nitric oxide synthase; MACS; Magnetic cell sorting; Myeloid dendritic cell; NK; Natural killer; PASI; PMA; Phorbol 12-myristate 13-acetate; Psoriasis; Psoriasis Area and Severity Index; Soluble TNF-α (17 kDa); TNF receptor; TNF-α; TNFR; TUNEL; Terminal deoxynucleotidyl transferase dUTP nick end labeling; Transmembrane TNF-α (26 kDa); iNOS; mDC; myeloid dendritic cells; sTNF-α; slan; tmTNF-α