title: 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.
authors.affiliation: Pharmazentrum Frankfurt/Das Zentrum für Arzneimittelforschung, Entwicklung und -Sicherheit, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Christine V
authors.initials: CV
authors.lastname: Möser
authors.forename: Katharina
authors.initials: K
authors.lastname: Kynast
authors.forename: Katharina
authors.initials: K
authors.lastname: Baatz
authors.forename: Otto Quintus
authors.initials: OQ
authors.lastname: Russe
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.forename: Heike
authors.initials: H
authors.lastname: Costiuk
authors.forename: Ruirui
authors.initials: R
authors.lastname: Lu
authors.forename: Achim
authors.initials: A
authors.lastname: Schmidtko
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000201:enzymology* / Q000209:etiology; D051550:I-kappa B Kinase / Q000378:metabolism*; D017403:In Situ Hybridization; D007249:Inflammation / Q000150:complications / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051550:I-kappa B Kinase