IKIP Negatively Regulates NF-κB Activation and Inflammation through Inhibition of IKKα/β Phosphorylation

Stringent regulation of the transcription factor NF-kappaB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-kappaB activation. IKIP interacted with IKKalpha/beta to block its association with NEMO, thereby inhibiting the phosphorylation of IKKalpha/beta and the activation of NF-kappaB. Upon LPS, TNF-alpha, and IL-1beta stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKalpha/beta phosphorylation, IkappaB, and p65 phosphorylation and production of NF-kappaB-responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate-induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-kappaB activation by inhibition of IKKalpha/beta phosphorylation through the disruption of IKK complex formation.