When exposed to the bacterial endotoxin, lipopolysaccharide (LPS), human monocytes are activated to coordinately express multiple cytokines. Most of these are early response genes whose products in turn activate expression of other genes at tissue sites often far removed from the focus of initial monocyte activation. Interleukin-10 (IL-10) is also induced by LPS, but unlike other LPS-inducible cytokines, it feedback inhibits monocyte activation by down-regulating expression of many cytokines. In this project, we are examining the factors that regulate endogenous IL-10 synthesis in human monocytes, as well as the mechanism by which IL-10 suppresses expression of various LPS-inducible genes, particularly tumor necrosis factor (TNF), in human monocytes. Determining how IL-10 inhibits proinflammatory cytokine expression in human monocytes is critical to our understanding of the mechanism of action of this cytokine. This information may be useful when evaluating any therapeutic activity observed in future clinical trials. Interleukin-10 (IL-10) is a relatively recently discovered cytokine that inhibits production of many proinflammatory cytokines, including TNF, IL-1 and IL-6, in human monocytes. Relatively little is known about mechanism of action of this cytokine or the factors that control its expression in activated monocytes. IL-10 is currently being tested as a potential antiinflammatory agent for the treatment of a number of inflammatory diseases. Analysis of the factors that regulate IL-10 expression in human monocytes may provide important information regarding the role of this cytokine in suppressing proinflammatory cytokine synthesis in vivo. It may also help CBER staff to more critically evaluate future clinical trials of IL-10. Furthermore, analysis of the effects of IL-10 on cytokine expression in vitro may help to identify surrogate markers of IL-10 activity that may be useful in monitoring the potency of recombinant IL-10 in human recipients.
