The use of cytokines as therapeutic agents is complicated by the fact that they do not act in isolation. The dissection of cytokine networks reveals that most cytokines are highly regulated in response to the levels of other cytokines. The current focus is on LPS-mediated responses of human monocytes and their modulation by stimuli that affect monocyte differentiation, particularly interferon-gamma and colony-stimulating factors. This work has revealed that the induction of critical bio-active cytokines from monocytes can be highly influenced by the presence of these exogenous cytokines. The dependence upon, and effects of, priming differ with each monokine examined. For example, IL-12 is induced only after IFN-gamma priming, while IFN-alpha is induced following priming with either IFN-gamma or GM-CSF. Current studies are designed to identify critical intracellular factors that nediate these effects. This should provide useful information for understanding how cytokines interact in vivo, which should help predict the outome of in vivo responses to exogenous cytokines. This research reveals critical information about the capacity of specific cytokines to regulate the expression of other cytokines and affect differentiation of monocytes. Many of these cytokines are under current review in the division. We cannot have enough information about how these cytokines work in isolated circumstances, which gives rise to predictions about how they may function in vivo. In addition, this work requires continuing knowledge of methods for assessing the presence and activity of a variety of cytokines. Cytokine levels in sepsis patients have become important in patient monitoring and possibly in predicting outcome. Recent work in our laboratory is addressing the expression of IL-12 in dendritic cells. Currently, CBER is receiving numerous INDs proposing the use of dendritic cells in a variety of vaccines. Studies of IL-12 expression in dendritic cells will provide an excellent marker for the function and activity of these cells in vaccine products.
