TAK1 signaling is essential for macrophage survival

Macrophage survival is important for preventing invasion of microorganisms but is also causally associated with chronic inflammatory diseases. Bacterial moieties such as lipopolysaccaride (LPS) activates macrophages and modulates their survival. However, the pathway regulating macrophage survival is not fully understood. TAK1 (TGFβ activated kinase 1) is an essential signaling intermediate in LPS‐induced immune responses. TAB1 (TAK1 binding protein 1) is an activator of TAK1; but its physiological role has not been determined. We characterized macrophages having inducible gene deletion of tak1 and tab1. TAK1 but not TAB1 deficiency caused spontaneous apoptosis within 4 days after induction of gene deletion. However, we found that TAB1‐deficient but not wild type macrophages underwent cell death upon LPS treatment. These results suggest that both TAB1‐dependent and ‐independent TAK1 activity regulate macrophage survival, and that TAB1‐dependent activation of TAK1 is required for survival of activated macrophages. We are currently investigating the mechanism of LPS‐induced TAB1‐dependent activation of TAK1. Because TAB1 deficiency kills only activated macrophages, TAB1 may be a novel target for treatment of chronic inflammation and sepsis. This work was supported by NIH GM068812 and GM084406 (to J. N‐T.)