| First Author | Möser CV | Year | 2011 |
| Journal | J Immunol | Volume | 187 |
| Issue | 5 | Pages | 2617-25 |
| PubMed ID | 21813779 | Mgi Jnum | J:179267 |
| Mgi Id | MGI:5301521 | Doi | 10.4049/jimmunol.1004088 |
| Citation | Moser CV, et al. (2011) The protein kinase IKKepsilon is a potential target for the treatment of inflammatory hyperalgesia. J Immunol 187(5):2617-25 |
| abstractText | Inhibitor-kappaB kinase epsilon (IKKepsilon) was only recently identified as an enzyme with high homology to the classical I-kappaB kinase subunits, IKKalpha and IKKbeta. 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 IKKepsilon plays a role in the regulation of NF-kappaB activity, but the distinct mechanisms of IKKepsilon-mediated NF-kappaB activation are not clear. Given the paramount role of NF-kappaB in inflammation, we investigated the regulation and function of IKKepsilon in models of inflammatory hyperalgesia in mice. We found that IKKepsilon was abundantly expressed in nociceptive neurons in the spinal cord and in dorsal root ganglia. IKKepsilon mRNA and protein levels rapidly increased in spinal cord and dorsal root ganglia during hind paw inflammation evoked by injection of zymosan or formalin. IKKepsilon knockout mice showed normal nociceptive responses to acute heat or mechanical stimulation. However, in inflammatory pain models, IKKepsilon-deficient mice exhibited a significantly reduced nociceptive behavior in comparison with wild type mice, indicating that IKKepsilon contributed to the development of inflammatory hyperalgesia. Antinociceptive effects were associated with reduced activation of NF-kappaB and attenuated NF-kappaB-dependent induction of cyclooxygenase-2, inducible NO synthase, and metalloproteinase-9. In contrast, IRF-3, which is an important IKKepsilon target in viral infections, was not regulated after inflammatory nociceptive stimulation. Therefore, we concluded that IKKepsilon modulates inflammatory nociceptive sensitivity by activation of NF-kappaB-dependent gene transcription and may be useful as a therapeutic target in the treatment of inflammatory pain. |
