[PDF][PDF] TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1+ CD11b+ neutrophils

AA Ajibade, Q Wang, J Cui, J Zou, X Xia, M Wang… - Immunity, 2012 - cell.com
AA Ajibade, Q Wang, J Cui, J Zou, X Xia, M Wang, Y Tong, W Hui, D Liu, B Su, HY Wang…
Immunity, 2012cell.com
Stringent control of NF-κB and mitogen-activated protein kinase (MAPK) signaling is critical
during innate immune responses. TGF-β activated kinase-1 (TAK1) is essential for NF-κB
activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific
deletion of TAK1 (Map3k7 ΔM/ΔM) 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 …
Summary
Stringent control of NF-κB and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-β activated kinase-1 (TAK1) is essential for NF-κB activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7ΔM/ΔM) 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-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7ΔM/ΔM mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1β, IL-6, and TNF-α in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7ΔM/ΔM 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.
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