Interleukin-1 (IL-1) mediates numerous host responses through the rapid activation of nuclear factor-κB (NF-κB), but the signal pathways leading to NF-κB activation are regulated at multiple stages. Here, we propose a novel regulatory system for IL-1-induced NF-κB activation by a tyrosine kinase, c-Src. The kinase activity of c-Src increases in an IL-1-dependent manner and the ectopic expression of c-Src augments IL-1-induced NF-κB activation, suggesting the involvement of c-Src in IL-1 signaling. However, a Src family inhibitor, PP2 failed to inhibit IL-1-induced NF-κB activation, and the expression of a c-Src mutant lacking kinase activity (c-Src KD) augmented IL-1-induced NF-κB activation as well as wild type c-Src, indicating that the tyrosine kinase activity is not required for IL-1-induced NF-κB activation. Furthermore, a physiological interaction between c-Src and Iκc;B kinase γ (IKKγ) was observed, implying the involvement of c-Src in the IKK-complex. While c-Src augmented IL-1-induced IKK activation independent of its kinase activity, the region comprising amino acids 361-440 in the c-Src kinase domain are required for NF-κB; activation. The same region of c-Src is also required for IL-1-induced IKK activation and the association with IKKγ. Taken together, our results suggest that c-Src plays a critical role in IL-1-induced NF-κB activation through the IKK complex.
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