Bacterial infection induces a host response that is, in many cases, protective, but in some situations, the host response to infection results in the sepsis syndrome of shock and organ failure. We have found that bDNA (but not mammalian DNA) activates macrophages to secrete IL-12 which, in turn, drives NK cell IFN-gamma secretion. Our most recent studies show that B cell-derived IL-10 plays a critical role as an inhibitor of bDNA induced inflammatory cytokines. Even though the effects of bDNA are LPS-independent, the activated cells (macrophages, B calls) and the cytokines produced (IL-12, TNF alpha, IL-6) follow a pattern remarkably similar to that seen following LPS stimulation. The goal of this proposal is to define mechanisms which distinguish bDNA- mediated activation from potential activation by LPS.
Specific aims i nclude: 1. Definition of the role of CD14/LBP in bDNA induced actuation 2. Identify the factor(s) which together with NF-kappaB induce IL-12 P40 transcription. 3. Define how bDNA differ from LPS with respect to early events in cell activation. These studies will better define the mechanism(s) of bDNA-induced cytokine production and will help guide studies directed at either inhibiting these cytokines (as in sepsis) or augmenting them (as vaccine adjuvants).
