The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation

Mechanisms of fulminant gene induction during an inflammatory response were investigated using expression of the chemoattractant cytokine interleukin- 8 (IL-8) as a model. Recently we found that coordinate activation ofNF-kapp aB and c-Jun N-terminal protein kinase (JNK) is required for strong IL-8 tr anscription, whereas the p38 MAP kinase (MAPK) pathway stabilizes the IL-8 mRNA It is unclear how these pathways are coupled to the receptor for IL-1, an important physiological inducer of IL-8. Expression of the MAP kinase k inase kinase (MAPKKK) TAK1 together with its coactivator TAB1 in HeLa cells activated all three pathways and was sufficient to induce IL-8 formation, NF-kappaB + JNK2-mediated transcription from a minimal IL-8 promoter, and p 38 MAPK-mediated stabilization of a reporter mRNA containing IL-8-derived r egulatory mRNA sequences. Expression of a kinase-inactive mutant of TAK1 la rgely blocked IL-1-induced transcription and mRNA stabilization, as well as formation of endogenous IL-8. Truncated TAB1, lacking the TAK1 binding dom ain, or a TAK1-derived peptide containing a TAK1 autoinhibitory domain were also efficient in inhibition. These data indicate that the previously desc ribed three-pathway model of IL-8 induction is operative in response to a p hysiological stimulus, IL-1, and that the MAPKKK TAK1 couples the IL-1 rece ptor to both transcriptional and RNA-targeted mechanisms mediated by the th ree pathways.