The Protein Kinase IKKε Is a Potential Target for the Treatment of Inflammatory Hyperalgesia

Inhibitor-kB kinase epsilon (IKK epsilon) was only recently identified as an enzyme with high homology to the classical I-kappa B kinase subunits, IKK alpha and IKK beta. Despite this similarity, it is mainly discussed as a repressor of viral infections by modulating type I IFNs. However, in vitro studies also showed that IKK epsilon plays a role in the regulation of NF-kappa B activity, but the distinct mechanisms of IKK epsilon -mediated NF-kappa B activation are not clear. Given the paramount role of NF-kappa B in inflammation, we investigated the regulation and function of IKK epsilon in models of inflammatory hyperalgesia in mice. We found that IKK epsilon was abundantly expressed in nociceptive neurons in the spinal cord and in dorsal root ganglia. IKK epsilon mRNA and protein levels rapidly increased in spinal cord and dorsal root ganglia during hind paw inflammation evoked by injection of zymosan or formalin. IKK epsilon knockout mice showed normal nociceptive responses to acute heat or mechanical stimulation. However, in inflammatory pain models, IKK epsilon deficient mice exhibited a significantly reduced nociceptive behavior in comparison with wild type mice, indicating that IKK epsilon contributed to the development of inflammatory hyperalgesia. Antinociceptive effects were associated with reduced activation of NF-kappa B and attenuated NF-kappa B-dependent induction of cyclooxygenase-2, inducible NO synthase, and metalloproteinase-9. In contrast, IRF-3, which is an important IKK epsilon target in viral infections, was not regulated after inflammatory nociceptive stimulation. Therefore, we concluded that modulates inflammatory nociceptive sensitivity by activation of NF-kappa B-dependent gene transcription and may be useful as a therapeutic target in the treatment of inflammatory pain. The Journal of Immunology, 2011, 187: 2617-2625.