02630nas a2200325   4500000000100000008004100001260001300042653002000055653001400075653003100089653001100120653002400131653001400155653002400169653002500193653003500218653003500253653002400288100001500312700001400327700001400341700001800355700001300373700001200386245009200398300001200490490000700502520178100509022001402290       2010                            d  c2010 Jan10aCells, Cultured10aCytokines10aGene Expression Regulation10aHumans10aLipopolysaccharides10aMonocytes10aMycobacterium bovis10aMycobacterium leprae10aNod2 Signaling Adaptor Protein10aPhosphatidylinositol 3-Kinases10aToll-Like Receptors1 aSinsimer D1 aFallows D1 aPeixoto B1 aKrahenbuhl JL1 aKaplan G1 aManca C00aMycobacterium leprae actively modulates the cytokine response in naive human monocytes.  a293-3000 v783 a<p>Leprosy is a chronic but treatable infectious disease caused by the intracellular pathogen Mycobacterium leprae. Host immunity to M. leprae determines the diversity of clinical manifestations seen in patients, from tuberculoid leprosy with robust production of Th1-type cytokines to lepromatous disease, characterized by elevated levels of Th2-type cytokines and a suboptimal proinflammatory response. Previous reports have indicated that M. leprae is a poor activator of macrophages and dendritic cells in vitro. To understand whether M. leprae fails to elicit an optimal Th1 immune response or actively interferes with its induction, we have examined the early interactions between M. leprae and monocytes from healthy human donors. We found that, in naïve monocytes, M. leprae induced high levels of the negative regulatory molecules MCP-1 and interleukin-1 (IL-1) receptor antagonist (IL-1Ra), while suppressing IL-6 production through phosphoinositide-3 kinase (PI3K)-dependent mechanisms. In addition, low levels of proinflammatory cytokines were observed in association with reduced activation of nuclear factor-kappaB (NF-kappaB) and delayed activation of IL-1beta-converting enzyme, ICE (caspase-1), in monocytes stimulated with M. leprae compared with Mycobacterium bovis BCG stimulation. Interestingly, although in itself a weak stimulator of cytokines, M. leprae primed the cells for increased production of tumor necrosis factor alpha and IL-10 in response to a strongly inducing secondary stimulus. Taken together, our results suggest that M. leprae plays an active role to control the release of cytokines from monocytes by providing both positive and negative regulatory signals via multiple signaling pathways involving PI3K, NF-kappaB, and caspase-1.</p>  a1098-5522