Mediator cyclin-dependent kinases upregulate transcription of inflammatory genes in cooperation with NF-κB and C/EBPβ on stimulation of Toll-like receptor 9.
In eukaryotes, the Mediator complex has important roles in regulation of transcription by RNA polymerase II. Mediator is a large complex with more than 20 subunits that form head, middle, tail and CDK/cyclin modules. Among them, CDK8 and/or CDK19 (CDK8/19), and their counterpart cyclin C, form the CDK/cyclin module together with Mediator subunits MED12 and MED13. Despite evidences of both activation and repression, the precise functional roles of CDK8/19 in transcription are still elusive. Our previous results indicate that CDK8/19 recruits epigenetic regulators to repress immunoresponse genes. Here, this study focused on Toll-like receptors (TLRs), which exert innate immune responses through recognition of pathogen-associated molecular patterns and examined the functional roles of CDK8/19. As a result, CDK8/19 regulated transcription of inflammatory genes on stimulation of TLR9 in myeloma-derived RPMI8226 cells, which led to expression of inflammation-associated genes such as IL8, IL10, PTX3 and CCL2. Mediator subunits CDK8/19 and MED1, inflammation-related transcriptional activator NF-κB and C/EBPβ, and general transcription factors TFIIE and TFIIB colocalized at the promoter regions of these genes under this condition. Our results show that CDK8/19 positively regulates inflammatory gene transcription in cooperation with NF-κB and C/EBPβ on stimulation of TLR9.
Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.|Research and Development Center, Fuso Pharmaceutical Industries, LTD., 2-3-30 Morinomiya, Joto-ku, Osaka, 536-8523, Japan.
Seiji
S
Yamamoto
Research and Development Center, Fuso Pharmaceutical Industries, LTD., 2-3-30 Morinomiya, Joto-ku, Osaka, 536-8523, Japan.
Tomoko
T
Hagihara
Research and Development Center, Fuso Pharmaceutical Industries, LTD., 2-3-30 Morinomiya, Joto-ku, Osaka, 536-8523, Japan.
Yoshiyuki
Y
Horiuchi
Research and Development Center, Fuso Pharmaceutical Industries, LTD., 2-3-30 Morinomiya, Joto-ku, Osaka, 536-8523, Japan.
Akira
A
Okui
Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Shotaro
S
Wani
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 153-8501, Japan.
Tokuyuki
T
Yoshida
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 153-8501, Japan.
Takao
T
Inoue
Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Aki
A
Tanaka
Department of Biochemistry, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
Takashi
T
Ito
Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Yutaka
Y
Hirose
Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.|Department of Biochemistry, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
Yoshiaki
Y
Ohkuma
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; C584437:CDK19 protein, human; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases