Cyclosporin A enhances IL-12 production by CpG motifs in bacterial DNA and synthetic oligodeoxynucleotides

Certain sequences of nucleotides (CpG moths) 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-IO 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-18 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-IO acts as a negative feedback regulator of CPG DNA-induced IL-12 production.