STAT4 is required for antibacterial defense but enhances mortality during polymicrobial sepsis

The signal transducer and activator of transcription factor 4 (STAT4) pathw ay mediates the intracellular effects of interleukin-12 (IL-12), leading to the production of gamma interferon, induction of a T helper type 1 respons e, and increased natural killer cell cytotoxicity. The purpose of this stud y was to determine the role of the STAT4 pathway during polymicrobial perit onitis in the cecal ligation and puncture (CLP) model. CLP was performed on STAT4-deficient (STAT4(-/-)) and wild-type control (BALB/c) mice. At 4 h a fter CLP, STAT4(-/-) mice had significantly higher bacterial counts in the peritoneal lavage fluid, liver, and blood. This difference persisted for 18 h in the peritoneal lavage fluid and blood. Neutrophil migration to the si te of infection and into remote tissues was unaffected. Despite higher bact erial counts locally and systemically, STAT4(-/-) mice had a lower mortalit y rate than BALB/c controls. In contrast, blockade of IL-12 in BALB/c mice was detrimental to host survival. A blunted serum IL-12 response at 18 h af ter CLP was exhibited in STAT4(-/-) mice. These results suggest several cri tical roles for the STAT4 pathway in the resolution of polymicrobial infect ions. Additionally, the disparate effects observed with IL-12 blockade and STAT4 deficiency on host survival suggest that IL-12 may activate alternate pathways promoting survival.