Regulation of innate immune response by Stat proteins during septic peritonitis

The immune response is generally divided into two types, termed type-1 and type-2 responses. The type-1 cytokine response is important in local host defense, while the type-2 cytokine response plays a protective role when microbes have disseminated into the body. Signal transducer and activator of transcription (Stat) proteins are involved in cytokine signal transduction. Stat3, Stat4 and Stat6 are members of this family essential in mediating responses to IL-10, IL-12 and IL-13, respectively. Here, we demonstrated the regulation of innate immunity by Stat proteins during septic peritonitis. Stat4^−/− and Stat6^−/− mice were resistant to septic peritonitis, whereas mice lacking Stat3 in macrophages and neutrophils (conditional Stat3^−/− mice) succumbed to the lethality. In an attempt to understand the mechanism, we elucidated that Stat4^−/− and Stat6^−/− mice were resistant to septic peritonitis by modulating systemic organ damage and enhancing local bacterial clearance, respectively, via balancing cytokine responses. Conditional Stat3^−/− mice displayed uncontrollable inflammatory responses during septic peritonitis, which were associated with significant increases in local and systemic levels of inflammatory cytokines. Thus, Stat proteins have a significant impact on innate immunity during sepsis, suggesting a possibility that regulation of Stat proteins may pave the way for novel therapeutic interventions in sepsis.