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Background: TANK-binding kinase (TBK1) is a non-canonical IκB kinase (IKK) involved in the regulation of type I interferons and of NF-κB signal transduction. It is activated by viral infections and inflammatory mediators and has therefore been associated with viral diseases, obesity, and rheumatoid arthritis. Its role in pain has not been investigated so far. Due to the important roles of NF-κB, classical IκB Kinases and the IKK-related kinase, IKKε, in inflammatory nociception, we hypothesized that TBK1, which is suggested to form a complex with IKKε under certain conditions, might also alter the inflammatory nociceptive response., Methods: We investigated TBK1 expression and regulation in "pain-relevant" tissues of C57BL/6 mice by immunofluorescence, quantitative PCR, and Western blot analysis. Furthermore, nociceptive responses and the underlying signal transduction pathways were assessed using TBK1(-/-) mice in two models of inflammatory nociception., Results: Our data show that TBK1 is expressed and regulated in the spinal cord after peripheral nociceptive stimulation and that a deletion of TBK1 alleviated the inflammatory hyperalgesia in mice while motor function and acute nociception were not altered. TBK1-mediated effects are at least partially mediated by regulation of NF-κB dependent COX-2 induction but also by alteration of expression of c-fos via modulation of MAP kinases as shown in the spinal cord of mice and in cell culture experiments., Conclusion: We suggest that TBK1 exerts pronociceptive effects in inflammatory nociception which are due to both modulation of NF-κB dependent genes and regulation of MAPKs and c-fos. Inhibition of TBK1 might therefore constitute a novel effective tool for analgesic therapy.

The transcription factor NF-κB was discovered in 1986 and since then has been extensively studied in relation to cancer research and inflammatory or autoimmune diseases due to its important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. Although much is known about NF-κB signaling, novel NF-κB functions in different diseases are still being uncovered, together with its target proteins, interaction partners and regulators of its activation cascade. Proteomic approaches are particularly suited to the discovery of new proteins involved in distinct signal transduction cascades. This review provides an update on and extension of a recent review that summarized a number of proteomic approaches to NF-κB signaling. The studies discussed here utilized innovative techniques and offer several new hypotheses on the role of NF-κB in physiological and pathophysiological processes, which open new avenues for research on NF-κB in the future.

NF-kappaB is a transcription factor that plays important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. Consequently, dysregulations in the NF-kappaB activation cascade have been associated with the pathogenesis of several diseases such as cancer, atherosclerosis and rheumatoid arthritis. Although NF-kappaB signaling pathways have been extensively investigated in this context, its varying components and targets are far from being completely elucidated. There is still an urgent need for the detection of novel NF-kappaB target proteins, novel interaction partners and novel regulators in the activation cascade, in particular with regard to its role in the aforementioned diseases. Therefore, several groups have performed different proteomic approaches to further investigate NF-kappaB signal transduction pathways. Most of these studies have been carried out in the area of cancer research; however, there are also several analyses in the field of inflammatory or autoimmune diseases. Furthermore, there have been a number of basic investigations that principally examined binding partners or so far unknown target proteins of NF-kappaB-related proteins. With these approaches, a number of novel and interesting proteins have been found that interfere with NF-kappaB signal transduction and might have an impact on NF-kappaB-related diseases. The results of these studies are summarized and discussed in this review.

Several studies indicate that the nuclear factor-kappa B (NF-kappaB) -activation cascade plays a crucial role not only in immune responses, inflammation, and apoptosis but also in the development and processing of pathological pain. Accordingly, a pharmacological intervention into this pathway may have antinociceptive effects and could provide novel treatment strategies for pain and inflammation. In this review we summarize the role of NF-kappaB in the nervous system, its impact on nociception, and several approaches that investigated the effects of various modulators of the classical I-kappaB-kinase-NF-kappaB signal transduction pathway in inflammatory nociception and neuropathic pain. The results indicate that NF-kappaB has an impact on nociceptive transmission and processing and that a number of substances that inhibit the NF-kappaB-activating cascade are capable of reducing the nociceptive response in different animal models. Therefore, a modulation of specific participants in the NF-kappaB signal transduction might exert a useful approach for the development of new painkillers.

Rofecoxib is a selective cyclooxygenase (COX)-2 inhibitor approved for the treatment of pain and inflammation in rheumatoid and osteoarthritis. Daily doses between 12.5 and 50 mg were found to reduce pain and inflammation, however, without a clear dose-effect relationship. Interestingly, rofecoxib treatment is associated with an unexpected incidence of renal adverse events compared with other COX inhibitors. Here, the effects of rofecoxib on the transcription factors nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) were analyzed to find out whether transcriptional changes might explain the lack of clear dose dependency and the occurrence of renal side effects. In vitro, rofecoxib dose dependently inhibited DNA binding capacity of NF-kappaB at doses of 10 to 100 microM, whereas the binding activity of AP-1 was considerably increased at 100 microM. In vivo, the anti-inflammatory effect of rofecoxib was equal at 1 and 10 mg/kg, whereas 50 mg/kg caused a significant further reduction of a zymosan-induced paw edema. This was associated with a clear decrease of inducible nitric oxide synthase (iNOS) protein expression in the spinal cord at this dose. At 1 and 10 mg/kg, however, iNOS was increased but COX-2 was decreased. Thus, the expression of proinflammatory proteins was similarly inconsistent as transcription factor regulation. In conclusion, the opposite effects of rofecoxib on AP-1 and NF-kappaB may explain the lack of clear dose dependency with rofecoxib in clinical studies or animal experiments. The effects on AP-1 may possibly affect renal sodium transport because certain renal sodium channels are regulated through AP-1. Transcription factor regulation might therefore influence both wanted and unwanted effects of rofecoxib.