Activation, cytokine production, and intracellular survival of bacteria in Salmonella-infected human monocyte-derived macrophages and dendritic cells

Salmonella enterica serovar typhimurium (S. typhimurium) is an intracellular pathogen causing localized gastroenteritis in humans. Macrophages (M phi s) and dendritic cells (DCs) play an important role in innate immunity against Salmonella. In this report, we have compared the consequences of infection of human X phi s and DCs with wild-type S. typhimurium and an isogenic PgtE-defective strain. PgtE is an outer membrane protein hypothesized to have a role in intracellular survival of Salmonella. We observed that DCs undergo full maturation in response to Salmonella infection, as indicated by up-regulation of cell-surface marker proteins CD80, CD83, CD86, and human leukocyte antigen class II. CC chemokine ligand 5 (CCL5), CXC chemokine ligand 10, tumor necrosis factor alpha, interleukin (IL)-12, and IL-18 gene expression and protein production were readily induced by Salmonella-infected M phi s and DCs. CCL20 was preferentially produced by M phi s, whereas DCs secreted higher levels of CCL19 as compared with M phi s'. DCs and M phi s infected with S. typhimurium also produced high levels of interferon-gamma (IFN-gamma). Cytokine neutralization and stimulation experiments suggest that the production was partly regulated by Salmonella-induced type I IFNs, IL-12, and IL-18. DC cytokine production induced by Salmonella was much higher as compared with the responses induced by Salmonella lipopolysaccharide or flagellin. M phi s and DCs were capable of internalizing and harboring Salmonella for several days. S. enterica PgtE provided no survival advantage for the bacteria in human M phi s or DCs. Our results demonstrate that although M phi s and DCs share similar functions, they may have different roles during Salmonella infection as a result of differential production of certain chemokines and cytokines.