The pattern recognition molecules Nod1 and Nod2 play important roles in 
intestinal homeostasis; however, how these proteins impact on the development of 
inflammation during bacterial colitis has not been examined. In the 
streptomycin-treated mouse model of Salmonella colitis, we found that mice 
deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced 
levels of inflammatory cytokines, and increased colonization of the mucosal 
tissue. Nod1 and Nod2 from both hematopoietic and nonhematopoietic sources 
contributed to the pathology, and all phenotypes were recapitulated in mice 
deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 
was strictly dependent on infection conditions that favored expression of the 
Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as 
Rip2 was dispensable for inflammation when mice were infected with bacteria 
grown under conditions that promoted expression of the SPI-1 TTSS. Thus, Nod1 
and Nod2 can modulate inflammation and mediate efficient clearance of bacteria 
from the mucosal tissue during Salmonella colitis, but their role is dependent 
on the expression of the SPI-2 TTSS.