CpG DNA induced IL-12 p40 gene activation is independent of STAT1 activation or production of interferon consensus sequence binding protein.

The host immune system responds to CpG motifs in bacterial DNA by rapidly producing proinflammatory cytokines. The host response to CpG DNA resembles, in many ways, the response to bacterial lipopolysaccharide (LPS). While both agents can induce a powerful inflammatory response, CpG DNA promotes Th1 and suppresses Th2 immunity. The regulation of macrophage IL-12 p40 secretion in response to stimulation with LPS and interferon-gamma (IFN-gamma) is dependent on the action of a nuclear transacting factor, interferon consensus sequence binding protein (ICSBP), a STAT1-dependent gene product. We found that CpG DNA induced IL-12 p40 secretion by macrophages from mice with either disrupted STAT1 or ICSBP genes. Additionally, CpG DNA did not induce translocation of transcription factors that bind to the gamma-activated sequence in the ICSBP gene nor did CpG DNA induce ICSBP transcription. CpG DNA, which activates macrophages by the TLR9 pathway, is a strong inducer of IL-12 p40, yet does so independently of IFN-gamma, STAT1 or ICSBP. Thus, CpG DNA-induced IL-12 p40 secretion is mediated by one or more signaling elements distinct from those induced by either LPS or IFN-gamma.

IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity.

Infections often precede the development of autoimmunity. Correlation between infection with a specific pathogen and a particular autoimmune disease ranges from moderately strong to quite weak. This lack of correspondence suggests that autoimmunity may result from microbial activation of a generic, as opposed to pathogen-specific host-defense response. The Toll-like receptors, essential to host recognition of microbial invasion, signal through a common, highly conserved pathway, activate innate immunity, and control adaptive immune responses. To determine the influence of Toll/IL-1 signaling on the development of autoimmunity, the responses of wild-type (WT) mice and IL-1R-associated kinase 1 (IRAK1)-deficient mice to induction of experimental autoimmune encephalomyelitis were compared. C57BL/6 and B6.IRAK1-deficient mice were immunized with MOG 35-55/CFA or MOG 35-55/CpG DNA/IFA. WT animals developed severe disease, whereas IRAK1-deficient mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation. IRAK1-deficient T cells also displayed impaired Th1 development, particularly during disease induction, despite normal TCR signaling. These results suggest that IRAK1 and the Toll/IL-1 pathway play an essential role in T cell priming, and demonstrate one means through which innate immunity can control subsequent development of autoimmunity. These findings may also help explain the association between antecedent infection and the development or exacerbations of some autoimmune diseases.