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

Abstract

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

IKKε Knockout Prevents High Fat Diet Induced Arterial Atherosclerosis and NF-κB Signaling in Mice

“…Thus, a limitation of our study was not being able to avoid the influence of the prevention of weight gain on the reduced NF-kB signaling and atherosclerosis in the DK mice. In spite of that, we could still reach an agreement that IKKε is a bridge between obesity and inflammation [33] and in many inflammatory diseases IKKε takes effect through the activation of NF-kB pathway signaling [22]–[23]. Further investigation is warranted to clarify the direct regulatory mechanism between IKKε and atherosclerosis.…”

“…This observation provided us with a new link between IKKε and HFD-induced atherosclerosis [21]. Furthermore, several studies have also suggested the potential role of IKKε in inflammatory pain, rheumatoid arthritis and osteoarthritis through the NF-κB activation cascade [22]–[23]. In this study, we therefore investigated whether IKKε plays a critical role in the initiation and progression of atherosclerosis through activation of the NF-κB pathway.…”

Drosophila caspase activity is required independently of apoptosis to produce active TNF/Eiger during nociceptive sensitization

“…27, 28 TNF signaling and NF- κ B are associated with both acute and chronic pain. 29, 30, 31, 32, 33, 34, 35 The transcriptional consequences of TNFR signaling and NF- κ B activation in damage-sensitized nociceptive sensory neurons, however, remain unclear.…”

Inhibitor Kappa B Kinase Beta Dependent Cytokine Upregulation in Nociceptive Neurons Contributes to Nociceptive Hypersensitivity After Sciatic Nerve Injury

“…unchanged amount of IKKb protein, total and phosphorylated, in the spinal cord after nerve injury and the only weak and transient increase of phosphorylated IkBa at this site. We showed recently that NF-kB activation in the spinal cord after nociceptive stimulation strongly depended on the IKK-related kinase IKKε, 33 which was abundantly expressed in neurons and glia 33 and might adopt some of the stimulus-dependent NF-kB activation at this site and may also be involved in the glia activation in the spinal cord after nerve injury.…”