IL-12, Independently of IFN-γ, Plays a Crucial Role in the Pathogenesis of a Murine Psoriasis-Like Skin Disorder

Abstract

The onset of acute psoriasis and the exacerbation of chronic psoriasis are often associated with a history of bacterial infection. We demonstrate that while only few scid/scid mice develop disease when CD4+CD45Rbhigh T cells are transferred alone, coadministration of LPS plus IL-12 or staphylococcal enterotoxin B into scid/scid mice 1 day after CD4+CD45Rbhigh T cell transfer greatly enhances disease penetrance and severity. Most importantly, the skin lesions induced by this method exhibit many of the histologic hallmarks observed in human psoriasis. Skin infiltrating CD4+ T cells were predominantly memory/effector cells (CD45Rblow) and exhibited a highly polarized Th1 phenotype. To test whether the development of pathogenic T cells was dependent on their production of IFN-γ, we transferred IFN-γ−/− CD4+CD45Rbhigh T cells into scid/scid or into T, B and NK cell-deficient scid/beige mice. Surprisingly, the incidence of psoriasis was similar to scid/scid animals that received IFN-γ+/+ T cells, although acanthosis of the skin was attenuated. In contrast, the development of psoriasis was abolished if anti-IL-12 mAb was administered on day 7 and 35 after T cell transfer. Skin-derived IFN-γ−/− inflammatory cells, but not cells from anti-IL-12-treated animals, secreted substantial amounts of TNF-α, suggesting that the inflammatory effect of IFN-γ−/− T cells may be partly exerted by TNF-α and that the therapeutic effect of anti-IL-12 may depend on its ability to down-regulate both TNF-α and IFN-γ. Overall, these results suggest that IL-12, independently of IFN-γ, is able to induce pathogenic, inflammatory T cells that are able to induce psoriasiform lesions in mice.

Natural Product-Derived Compounds Targeting Keratinocytes and Molecular Pathways in Psoriasis Therapeutics

“…IFN-γ plays a significant role in psoriasis pathogenesis as it is intricately involved in the complex interplay between IL-17 and IFN-γ-producing CD 4+ and CD 8+ T-cell subsets [ 37 ]. IFN-γ was initially considered a major driver of psoriasis owing to its upregulation in the IL-12/IFN-γ signaling pathway [ 38 ]. Elevated IFN-γ levels correlated with disease severity in both serum and skin samples [ 39 ].…”

Proteomic and Metabolomic Changes in Psoriasis Preclinical and Clinical Aspects

“…Typically, T-cells from HLA-B27 transgenic rats [56], CD+/CD45RBhi T-cells (naive T cells, e.g., from B10.D2 mice) [57], or Th17 cells from desmoglein 3-specific-tg mice (Dsg3H1-Th17) can be used [58]. As recipients, immunocompromised nontransgenic rats [59], scid/scid mice [56,60], or mice that produce no mature T cells or B cells (recombination activating gene 2, Rag2 −/− KO mice) can be used [61]. Shifting the immunological balance using T-cells gives the opportunity to analyze changes in immune cell response and pathways involved in these processes.…”

Novel antibodies that selectively block mouse IL‐12 enable the re‐evaluation of the role of IL‐12 in immune protection and pathology

“…Moreover, it contributes to anti‐tumor immunity by stimulating CTL and NK cells [9–12]. However, IL‐12 also contributes to numerous infectious and auto‐immune pathologies like Schwartzman reaction [13], psoriasis [14], myasthenia gravis [15], glomerulonephritis [16], and nephropathy [17]. It is obvious, therefore, that selective blocking of IL‐12 activity could have significant therapeutic potential.…”