ABSTRACT
Certain sequences of nucleotides (CpG motifs) in bacterial DNA or synthetic oligonucleotides (CpG DNA) promote the production of proinflammatory cytokines, including TNF-alpha, IFN-gamma, IL-6, and IL-12. Here we demonstrate that the immunosuppressant cyclosporin A (CsA) unexpectedly enhanced CpG DNA-induced IL-12 production in murine splenocytes. CsA did not inhibit CpG DNA-induced TNF-alpha or IL-6 production, but decreased the production of IFN-gamma by CpG DNA. Upon examining mechanisms by which CsA increases IL-12 production, we found that CpG DNA can also induce IL-10 production in B cells and that this production was sensitive to CsA. IL-10 has anti-inflammatory effects and can reduce the production of IL-12. To determine the possible role of CsA-modulated IL-10 production in mediating the increased IL-12 levels, splenocytes from IL-10 gene-disrupted mice (IL-10 -/-) and splenocytes cultured in anti-IL-10 Ab were studied. CpG DNA-stimulated IL-10 (-/-) splenocytes demonstrated no increase in IL-12 levels in the presence of CsA. Anti-IL-10 Ab treatment of normal splenocytes increased the magnitude of CpG DNA-induced IL-12 production to that seen with CsA. These results suggest that CpG DNA induces CsA-sensitive IL-10 production in B cells and that IL-10 acts as a negative feedback regulator of CpG DNA-induced IL-12 production.
Subject(s)
B-Lymphocytes/immunology , Cyclosporine/pharmacology , DNA, Bacterial/pharmacology , Immunosuppressive Agents/pharmacology , Interleukin-12/immunology , Lymphocyte Activation/drug effects , Oligonucleotides/pharmacology , Animals , B-Lymphocytes/drug effects , Cyclosporine/immunology , DNA, Bacterial/immunology , Drug Synergism , Escherichia coli , Immunosuppressive Agents/immunology , Interleukin-12/biosynthesis , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Oligonucleotides/immunologyABSTRACT
The fate of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) was studied by using aquatic sediment and lake water under laboratory conditions. Most of the TCDD was found in the sediment from which it slowly disappeared. Evaporation may be a major mode of disappearance of TCDD in samples incubated 39 days or more, with metabolism playing only a minor role. Under the experimental conditions the half-life of TCDD was in the order of 600 days. The metabolic activities were enhanced under conditions which stimulated microbial growth in the presence of sediment, and the metabolites were found to be released from the sediment to the ambient water.
