IL-1-induced NF kappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK)

Mutant I1A cells, lacking IL-1 receptor-associated kinase (IRAK) mRNA and p rotein, have been used to study the involvement of IRAK in NF kappaB and c- Jun N-terminal kinase (JNK) activation. A series of IRAK deletion construct s were expressed in I1A cells, which were then tested for their ability to respond to IL-1. Both the N-terminal death domain and the C-terminal region of IRAK are required for IL-1-induced NF kappaB and JNK activation, wherea s the N-proximal undetermined domain is required for the activation of NF k appaB but not JNK. The phosphorylation and ubiquitination of IRAK deletion mutants correlate tightly with their ability to activate NF kappaB in respo nse to IL-1, but IRAK can mediate IL-1-induced JNK activation without being phosphorylated. These studies reveal that the IL-1-induced signaling pathw ays leading to NF kappaB and INK activation diverge either at IRAK or at a point nearer to the receptor.