TAK1 negatively regulates NF-?B and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils.

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

SUBMITTER: Ajibade AA 

PROVIDER: S-EPMC3750978 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature