Subject(s)
ADAM17 Protein/metabolism , Extracellular Vesicles/virology , HIV Infections/virology , Host-Pathogen Interactions/physiology , Proto-Oncogene Proteins c-hck/metabolism , Case-Control Studies , Cell Line , Extracellular Vesicles/metabolism , Extracellular Vesicles/pathology , HIV Core Protein p24/metabolism , HIV Infections/pathology , Hepatocytes/metabolism , Hepatocytes/virology , Humans , Liver/metabolism , Liver/pathology , Liver/virology , Male , Myeloid Cells/metabolism , Myeloid Cells/virology , Proto-Oncogene Proteins c-hck/genetics , nef Gene Products, Human Immunodeficiency Virus/metabolismABSTRACT
In the present study we examined the role of thymic stromal lymphopoietin (TSLP) in experimental autoimmune encephalomyelitis (EAE). Here, we report that TSLP knock-out (KO) mice display a delayed onset of disease and an attenuated form of EAE. This delayed onset was accompanied by a reduced number of encephalitogenic T helper type 1 (Th1) cells in the central nervous system (CNS) of TSLP KO mice. In addition, CD4(+) and CD8(+) T cells from CNS of TSLP KO mice show a reduced activation status in comparison to wild-type mice. It is noteworthy that we could also show that lymph node cells from TSLP KO mice expanded less efficiently and that interleukin (IL)-6-, interferon (IFN)-γ and tumour necrosis factor (TNF)-α levels were reduced. Furthermore, CD3(+) T cells isolated in the preclinical phase from myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55))-immunized TSLP KO mice showed a reduced response after secondary exposure to MOG(35-55), indicating that differentiation of naive T cells into MOG(35-55)-specific effector and memory T cells was impaired in KO mice. The addition of recombinant TSLP enhanced T cell proliferation during MOG(35-55) restimulation, showing that T cells also respond directly to TSLP. In summary, these data demonstrate that expression of, and immune activation by, TSLP contributes significantly to the immunopathology of EAE.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytokines/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Th1 Cells/immunology , Animals , Bone Marrow Cells/immunology , Cell Proliferation , Cells, Cultured , Central Nervous System/immunology , Cytokines/deficiency , Cytokines/genetics , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/pathology , Inflammation/immunology , Interferon-gamma/metabolism , Interleukin-6/metabolism , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Peptide Fragments/immunology , Th1 Cells/cytology , Tumor Necrosis Factor-alpha/metabolism , Thymic Stromal LymphopoietinABSTRACT
The physiological balance between pro- and anti-inflammatory processes is dysregulated in inflammatory bowel diseases (IBD) as in Crohn's disease and ulcerative colitis. Conventional therapy uses anti-inflammatory and immunosuppressive corticosteroids to treat acute-phase symptoms. However, low remission rate and strong side effects of these therapies are not satisfying. Thus, there is a high medical need for new therapeutic strategies. Soluble CD83, the extracellular domain of the transmembrane CD83 molecule, has been reported to have interesting therapeutic and immunosuppressive properties by suppressing dendritic cell (DC)-mediated T-cell activation and inducing tolerogenic DCs. However, the expression and function of CD83 in IBD is still unknown. Here, we show that CD83 expression is upregulated by different leukocyte populations in a chemical-induced murine colitis model. Furthermore, in this study the potential of sCD83 to modulate colitis using an experimental murine colitis model was investigated. Strikingly, sCD83 ameliorated the clinical disease symptoms, drastically reduced mortality, and strongly decreased inflammatory cytokine expression in mesenteric lymph nodes and colon. The infiltration of macrophages and granulocytes into colonic tissues was vigorously inhibited. Mechanistically, we could show that sCD83-induced expression of indolamine 2,3-dioxygenase is essential for its protective effects.
