title: TANK-binding kinase 1 (TBK1) modulates inflammatory hyperalgesia by regulating MAP kinases and NF-κB dependent genes.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Christine V
authors.initials: CV
authors.lastname: Möser
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Stephan
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Altenrath
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kynast
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Otto Q
authors.initials: OQ
authors.lastname: Russe
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Olbrich
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany. e.niederberger@em.uni-frankfurt.de.
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism*; D007249:Inflammation / Q000150:complications* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D017288:Pain Threshold / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D033921:Vesicular Transport Proteins
chemical_list: D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D008840:Microfilament Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; C077623:Ptgs2 protein, mouse; C498588:Tbk1 protein, mouse; C527550:Ccdc88a protein, mouse; D033921:Vesicular Transport Proteins