title: Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.
abstract: Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.
authors.affiliation: Department of Medicine I and Department of Neurology, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bierhaus
authors.forename: S
authors.initials: S
authors.lastname: Schiekofer
authors.forename: M
authors.initials: M
authors.lastname: Schwaninger
authors.forename: M
authors.initials: M
authors.lastname: Andrassy
authors.forename: P M
authors.initials: PM
authors.lastname: Humpert
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Hong
authors.forename: T
authors.initials: T
authors.lastname: Luther
authors.forename: T
authors.initials: T
authors.lastname: Henle
authors.forename: I
authors.initials: I
authors.lastname: Klöting
authors.forename: M
authors.initials: M
authors.lastname: Morcos
authors.forename: M
authors.initials: M
authors.lastname: Hofmann
authors.forename: H
authors.initials: H
authors.lastname: Tritschler
authors.forename: B
authors.initials: B
authors.lastname: Weigle
authors.forename: M
authors.initials: M
authors.lastname: Kasper
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: G
authors.initials: G
authors.lastname: Perry
authors.forename: A M
authors.initials: AM
authors.lastname: Schmidt
authors.forename: D M
authors.initials: DM
authors.lastname: Stern
authors.forename: H U
authors.initials: HU
authors.lastname: Häring
authors.forename: E
authors.initials: E
authors.lastname: Schleicher
authors.forename: P P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005246:Feedback; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D051996:Transcription Factor RelA
chemical_list: D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D051996:Transcription Factor RelA; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D004247:DNA