cAMP-increasing agents such as prostaglandin E 2 (PGE 2) are known to protect against LPS-induced liver injury by down-regulating the production of inflammatory cytokines such as TNF-α. However, the effects of such reagents on host defense against bacterial infection remain unknown. We show here that in vivo administration of PGE 2 significantly protected mice against liver injury after Escherichia coli infection but hampered the resolution of the infection. PGE 2 significantly suppressed circulating TNF-α and IL-12 levels but increased the IL-10 production after E. coli challenge. PGE 2 inhibited the emergence of γδ T cells in the peritoneal cavity, which are important for host defense against E. coli, and deteriorated bacterial exclusion in the peritoneal cavity after E. coli challenge. These results suggested that PGE 2 affects host defense mechanisms against E. coli infection through modulation of cytokine production and γδ T cell accumulation.