Salmonella enterica serovar Typhimurium (S. typhimurium) and Yersinia enterocolitica are enteric pathogens capable of colonizing and inducing inflammatory responses in Peyer's patches (PPs) and mesenteric lymph nodes (MLNs). Although the tissue colonization pattern is similar between these two pathogens, their pathogenic lifestyles are quite different. For example, while S. typhimurium is primarily an intracellular pathogen, Y. enterocolitica survives primarily extracellularly. We determined and compared the transcriptional changes occurring in response to S. typhimurium and Y. enterocolitica colonization of PP using Affymetrix GeneChip technology. Both pathogens elicited a general inflammatory response indicated by the upregulation of cytokines and chemokines. However, specific differences were also observed, most notably in the transcriptional regulation of gamma interferon (IFN-gamma) and IFN-gamma-regulated genes in response to S. typhimurium but not Y. enterocolitica. Of particular note, a group of genes encoding matrix metalloproteinases (MMPs) had increased transcript numbers in the PPs following infection with both pathogens. The experiments described here compare oral S. typhimurium or Y. enterocolitica infection in stromelysin-1 (MMP-3)-deficient mice (mmp-3(-/-)) with mice possessing functional MMP-3 (mmp-3(+/+)). There was little difference in the survival of MMP-3-deficient mice infected with Y. enterocolitica when compared with littermate controls. Surprisingly though, mmp-3(-/-) mice were markedly more resistant to S. typhimurium infection than the control mice. S. typhimurium was able to colonize mmp-3(-/-) mice, albeit in a delayed fashion, to equivalent levels as mmp-3(+/+) mice. Nevertheless, significantly lower levels of inflammatory cytokines were detected in tissues and serum in the mmp-3(-/-) mice in comparison with mmp-3(+/+) mice. We hypothesize that MMP-3 is involved in initiating an early and lethal cytokine response to S. typhimurium colonization.