Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages

Background: The spectrum of TNF-alpha-producing cells in patients with psoriasis, as well as their fate during treatment with TNF-alpha antagonists, is not clearly defined. Objective: We sought to analyze the effects of anti-TNF-alpha treatment on TNF-alpha 1 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-alpha 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-alpha-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-alpha in other cells, including keratinocytes or T cells, making these cell types unlikely targets of TNF-alpha blockers. Up to 48 hours after the intravenous administration of the TNF-alpha antagonist infliximab, we encountered no overt changes in numbers of TNF-alpha 1 cells or signs of apoptosis in lesional psoriatic skin. Yet we observed a rapid decrease in IL-12p40, IL-1 beta, CCL20, and IL12RB1 mRNA levels. Consistently, TNF-alpha 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. Conclusion: The decrease in tissue inflammation during anti-TNF-alpha therapy is not due to immediate killing of TNF-alpha-producing cells but rather results from a rapid downregulation of the pathogenic IL-12/IL-23-driven immune response.