The physiological role of PAI-2 in endotoxin-induced sepsis

Introduction Sepsis caused by uncontrolled inflammation is the leading cause of death in intensive care units today, but no effective therapeutic medication is available currently. During microbial infections, pathogen-associated molecular patterns (PAMPs) are recognized by the host innate immune system, which then mounts a defensive response. Myeloid cells play central roles in PAMP recognition and in the initiation and amplification of inflammatory cascades. Recent studies indicate that a novel system termed the inflammasome carries out processing of cytoplasmic stored pro-IL-1 β , and pro-IL-18. Both IL-1 β and IL-18 are highly potent proinflammatory cytokines. In addition, inflammasome activation has also been linked to an increase of host-cell death in certain cell types. Therefore the regulation of activation of the inflammasome is very important, but its mechanism is unclear. Plasminogen activator inhibitor 2 (PAI-2), a member of a large group of proteins that inhibit serine proteases, is regulated by IKK β -dependent activation of the transcription factor NF- κ B. Previous studies have shown that mice with Ikkβ deletion in myeloid cells are hypersusceptible to endotoxin (LPS)-induced septic shock, and increased LPS susceptibility is associated with elevated plasma IL-1 β . Reconstitution of Ikkβ -deficient macrophages with PAI-2 blocks apoptosis and IL-1 β release. Theseresults suggest that PAI-2 modulatesendotoxin-induced IL-1 β production and apoptosis in macrophages. Methods To determine the physiological role of PAI-2 in vivo , we generatedtransgenic mice that specifically express PAI-2 in macrophages and neutrophils, and crossed this transgenic mice with mutant mice with Ikkβ deletion in myeloid cells. Results We are currently examining if myeloid deletion Ikkb mice restored PAI-2 expression can resist LPS-induced septic shock. In addition, we are also investigating the underlying mechanism by which PAI-2 regulates LPS-induced IL-1 β production. Conclusion Our data would reveal the functional role of myeloid-specific expression of PAI-2 in LPS-induced septic shock in vivo .