title: Involvement of DNA-PKcs in the IL-6 and IL-12 response to CpG-ODN is mediated by its interaction with TRAF6 in dendritic cells.
abstract: CpG-ODN stimulates dendritic cells (DCs) to produce cytokines, which are important for pathogenesis of autoimmune disorders and vaccine strategy for cancer. CpG-ODN activates the TLR9/MyD88/TRAF6 cascade leading to activation of IKK-NF-κB and JNK, which are critical for production of pro-inflammatory cytokines. However, whether other molecules are involved in activation of CpG-ODN signaling is still not clear. Here we report that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is involved in this activation process. DNA-PKcs-deficient DCs exhibited a defect in the IL-6 and IL-12 response to CpG-ODN in a dose- and time-dependent manner. Loss of DNA-PKcs impaired phosphorylation of IKK, IκBα, NF-κB and JNK in response to CpG-ODN. Interestingly, CpG-ODN was able to bind DNA-PKcs and induce its association and co-localization with TRAF6 in the absence of TLR9. Our data suggest that DNA-PKcs is a player in CpG-ODN signaling and may explain why DNA-PKcs is implicated in the pathogenic process of autoimmune disease.
authors.affiliation: Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.forename: Marianna
authors.initials: M
authors.lastname: Muranyi
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Chu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Chu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D018664:Interleukin-12 / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010766:Phosphorylation; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D048029:TNF Receptor-Associated Factor 6; D051217:Toll-Like Receptor 9; D018664:Interleukin-12; D051747:DNA-Activated Protein Kinase