TWEAK Regulates Cellular Immunity

TNF-related weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily, alias TNFSF12. The mouse gene was cloned by chance and the human gene was identified among EST clones. TWEAK is secreted by several cell types and binds, naturally, TWEAK-R, which is also known as FN14 because it is a 14 kDa protein that is inducible by fibroblast growth factor. FN14 is also distantly related to the TNFR family. Despite all this talk of families, TWEAK was an orphan when it came to functional relationships. Now, Maecker and colleagues report that TWEAK-knockout (TWEAK-KO) mice have altered immune systems. Specifically, the deficient mice have more natural killer cells and T helper type 1 (Th1) cells and their stimulated lymphocytes secrete more interferon-gamma and interleukin-12, suggesting that TWEAK normally acts to reduce these responses. TWEAK-KO mice succumb to shock caused by endotoxin, the bacterial cell wall component lipopolysaccharide (LPS), at lower doses than normal mice. On the other hand, TWEAK-KO mice resisted transplanted tumor cells better than normal mice. The authors also observed that TWEAK stimulates the rapid and prolonged association of NF-kappaB p65, a key transcription factor and intracellular signal, with the histone deacetylase HDAC-1, whereas TNF stimulates p65 association with the transciption coactivator p300. This intriguing observation is the likely molecular basis for the difference between TWEAK and TNF.
Maecker et al "TWEAK attenuates the transition from innate to adaptive immunity." Cell. 2005 123:931-44