4: Bacterial driven inhibition of IL-12p40 in primary human cells via modulation of IRF1 and IRF8 independent of GPCR signaling and IL-10

Abstract

IL-12 is an essential cytokine for defense against intracellular pathogens including the highly virulent Gram negative bacterium Francisella tularensis. A central mechanism of virulence embodied by F. tularensis is its ability to evade and suppress host inflammatory responses, including production of IL-12. The microbial component of F. tularensis and the mechanism by which this component interferes with IL-12 production have not been defined. Here we identify the class of microbial compounds and the molecular mechanism by which F. tularensis inhibits production of IL-12p40 in primary human dendritic cells (hDC). We show that lipid isolated from virulent F. tularensis recapitulates the profound suppression of IL-12p40 production observed in hDC infected with viable F. tularensis. Interference with IL-12p40 by F. tularensis is not mediated through G-protein coupled receptors, IL-10, TGF-β, or PGE2. We found that suppression of IL-12p40 by F. tularensis is mediated through inhibition of IRF1 translocation to host cell nuclei and interference with DNA binding of both IRF1 and IRF8 to the Ets2, but not the ISRE, region within the IL-12p40 promoter. Inhibition of IRF1 and IRF8 activity is selective since F. tularensis had no effect on activation of IRF3. These data demonstrate a novel mechanism by which a highly virulent bacterium interferes with cytokines required for protective Th1 type immunity.