TAK1 Negatively Regulates NF-κB and p38 MAP Kinase Activation in Gr-1+CD11b+ Neutrophils

Stringent control of NF-kappa B and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-beta activated kinase-1 (TAK1) is essential for NF-kappa B activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7(Delta M/Delta M)) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wildtype cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38, and JNK and the production of interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor-alpha (INF-alpha), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7(Delta M/Delta M) mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1 beta, IL-6, and TNF-alpha in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7(Delta M/Delta M) mice. Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner.