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Immunity. 2012 Jan 27;36(1):43-54. doi: 10.1016/j.immuni.2011.12.010. Epub 2012 Jan 5.

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

Author information

1
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.

Erratum in

  • Immunity. 2012 Jan 27;36(1):153.

Abstract

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 interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7(ΔM/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 Map3k7(ΔM/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.

PMID:
22226633
PMCID:
PMC3750978
DOI:
10.1016/j.immuni.2011.12.010
[Indexed for MEDLINE]
Free PMC Article

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