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The Journal of Immunology, 1998, 161: 3930-3935.
Copyright © 1998 by The American Association of Immunologists

Cyclosporin A Enhances IL-12 Production by CpG Motifs in Bacterial DNA and Synthetic Oligodeoxynucleotides1

Thomas W. Redford*, Ae-Kyung Yi{dagger}, Courtney T. Ward{dagger} and Arthur M. Krieg2,{dagger},{ddagger}

* University of Iowa College of Pharmacy and {dagger} Interdisciplinary Graduate Program in Immunology and Department of Internal Medicine, University of Iowa College of Medicine; Iowa City, IA 52242; and {ddagger} Department of Veteran Affairs Medical Center, Iowa City, IA 52246, and CpG ImmunoPharmaceuticals, Wellesley, MA 02481.

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.




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