Positive and negative regulation of pathogen induced dendritic cell function by G-protein coupled receptors

The induction of IL-12 from dendritic cells (DC) is a major initiating step in host resistance to intracellular pathogens. We have studied the regulation of this response using an in vivo model in which IL-12 production by splenic CD8alpha+ DC is followed after injection of a soluble extract (STAg) of the protozoan parasite Toxoplasma gondii. Our findings indicate that the potent IL-12 response observed is highly dependent on both the chemokine receptor CCR5 and G(i)-protein coupled signaling. In addition, we have examined the basis of the unresponsiveness of DC to secondary STAg injection which occurs following primary exposure to this parasite stimulus. Our results demonstrate that this refractory state correlates with the down-regulation of CCR5 expression on DC which, in turn, appears to depend on the induction of endogenous lipoxin A(4) (LXA(4)), a product of arachidonic acid metabolism. Since LXA(4) is known to also signal through a G-protein coupled receptor pathway, these findings taken together support a major role for G-protein signaling in the regulation of microbial-induced DC function.