The endotoxin (LPS) of Gram negative bacteria is a prototypic activator of the innate immune response. Recognition of LPS leads to upregulation of host defenses to limit infection, but may also lead to septic shock. Cells of myeloid lineage are central to this activation. Monocytes or macrophages (Mo) produce numerous inflammatory mediators including cytokines, bioactive lipids, degradative enzymes etc. In the case of cytokines, LPS induces gene expression via signaling pathways which are not well defined but appear to include serine/threonine kinases known as MAP kinases. It is proposed to study the role of one group of MAP kinases, p38, since they have been implicated in LPS-induced production of IL-1 and TNF. The major focus will be to identify substrates of p38 which control either transcriptional or post-transcriptional events associated with cytokine production. A combination of biochemical, immunologic and molecular biologic approaches will be used. These studies may lead to new approaches to control the injurious effects of LPS.