title: A Small Nuclear Acidic Protein (MTI-II, Zn2+Binding Protein, Parathymosin) That Inhibits Transcriptional Activity of NF-κB and Its Potential Application to Antiinflammatory Drugs.
abstract: Nuclear factor-κB (NF-κB) is the most potent proinflammatory transactivator, and an inhibitor of NF-κB is a good antiinflammatory drug. Glucocorticoids (GCs) are the strongest and the most frequently used antiinflammatory drugs. GC-bound glucocorticoid receptor (GR) inhibits the transcriptional activity of NF-κB and thereby suppresses a broad range of inflammatory processes. Concurrently, in whole body outside the inflammation area, the GR exerts a lot of hormone action, which results in severe side effects. There is a long-awaited need for a new NF-κB inhibitor. Previously we found a small nuclear acidic protein (named MTI-II, also known as Zn2+-binding protein or parathymosin), which worked as a coactivator of GR. Here we showed that overexpression of MTI-II inhibited a transcriptional activity of NF-κB independently of GCs and the GR. Vise versa, RNA interference suppression of inherent MTI-II enhanced the transcriptional activity of NF-κB. An immunoprecipitation analysis showed that MTI-II precipitated NF-κB after the stimulation of TNFα. Deletion mutants of MTI-II showed that central acidic region is essential for the inhibition of the transcriptional activity of NF-κB. These results suggest that MTI-II would be an inherent inhibitor that interacts with NF-κB. Next, we constructed MTI-II-based antiinflammatory drugs (three fusion proteins of MTI-II with a protein transduction domain and a fusion peptide of the central acidic region with protein transduction domain). These drugs had significant antiinflammatory effects on acute inflammation models and on animal models of human chronic inflammation diseases without an increase of the blood glucose level and repeated-dose toxicity. The MTI-II-based antiinflammatory drug will be a good alternative of GCs.
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Shizu
authors.initials: S
authors.lastname: Hirata-Tsuchiya
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kitamura
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Omoteyama
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sato
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Mitsumi
authors.initials: M
authors.lastname: Arito
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Manae S
authors.initials: MS
authors.lastname: Kurokawa
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Suematsu
authors.affiliation: Departments of Clinical Proteomics and Molecular Medicine (K.Ok., K.Om., T.S., M.A., N.S., T.K.) and Disease Biomarker Analysis and Molecular Regulation (M.S.K.), St Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan; Department of Biological Endodontics (S.H.-T.), Institute of Biomedical and Health Science, Hiroshima University, Hiroshima 734-8553, Japan; and Division of Endodontics and Restorative Dentistry (C.K.), Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kato
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013947:Thymosin / Q000031:analogs & derivatives* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D013947:Thymosin; C044498:parathymosin alpha