Human MSCs may respond to TLR ligation, and recent research has suggested that many tissues contain tissue-specific MSCs, possibly located in periendothelial and perivascular regions. At present, the functional consequences of these findings are unclear. We hypothesized that tissue-specific MSCs could play an instructional role during early phases of bacterial challenge. To investigate this hypothesis further, we set up a coculture system of glandular MSCs and peripheral blood neutrophils so that we could analyze the cellular interactions of these cells in response to LPS challenge. We found that stimulation with bacterial endotoxin induced chemokine receptor expression and mobility of MSCs. Activated MSCs secreted large amounts of inflammatory cytokines and recruited neutrophils in an IL-8- and MIF-dependent manner. Recruited and activated neutrophils showed a prolonged lifespan, an increased expression of inflammatory chemokines, and an enhanced responsiveness toward subsequent challenge with LPS. Our findings demonstrate a complex, functional interaction between tissue-resident MSCs and peripheral blood neutrophils upon bacterial challenge and suggest a role for MSCs in the early phases of pathogen challenge, when classical immune cells have not been recruited yet.