Diabetes-associated sustained activation of the transcription factor nuclear factor-κB

Angelika Bierhaus, Stephan Schiekofer, Markus Schwaninger, Martin Andrassy, Per M. Humpert, Jiang Chen, Mei Hong, Thomas Luther, Thomas Henle, Ingrid Klöting, Michael Morcos, Marion Hofmann, Hans Tritschler, Bernd Weigle, Michael Kasper, Mark Smith, George Perry, Ann Marie Schmidt, David Stern, Hans Ulrich Häring & 2 others Erwin Schleicher, Peter P. Nawroth

Research output: Contribution to journalArticle

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Abstract

Activation of the transcription factor nuclear factor-κB (NF-κB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-κB in vitro, we observed a long-lasting sustained activation of NF-κB in the absence of decreased IκBα in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-κBp65. A comparable increase in NF-κBp65 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-β peptide (Aβ) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-κB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a β-globin reporter transgene under control of NF-κB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-κB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-κB activation by ligands of RAGE was mediated by initial degradation of IκB proteins followed by new synthesis of NF-κBp65 mRNA and protein in the presence of newly synthesized IκBα and IκBβ. These data demonstrate that ligands of RAGE can induce sustained activation of NF-κB as a result of increased levels of de novo synthesized NF-κBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-κB activation observed in hyperglycemia and possibly other chronic diseases.

Original languageEnglish (US)
Pages (from-to)2792-2808
Number of pages17
JournalDiabetes
Volume50
Issue number12
DOIs
StatePublished - Jan 1 2001
Externally publishedYes

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Transcription Factors
Ligands
Transgenes
Messenger RNA
Advanced Glycosylation End Products
Globins
Diabetes Complications
Type 1 Diabetes Mellitus
Amyloid
Hyperglycemia
Proteolysis
Albumins
Cytoplasm
Proteins
Chronic Disease
Endothelial Cells
Antigens
Advanced Glycosylation End Product-Specific Receptor
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., ... Nawroth, P. P. (2001). Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. Diabetes, 50(12), 2792-2808. https://doi.org/10.2337/diabetes.50.12.2792

Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. / Bierhaus, Angelika; Schiekofer, Stephan; Schwaninger, Markus; Andrassy, Martin; Humpert, Per M.; Chen, Jiang; Hong, Mei; Luther, Thomas; Henle, Thomas; Klöting, Ingrid; Morcos, Michael; Hofmann, Marion; Tritschler, Hans; Weigle, Bernd; Kasper, Michael; Smith, Mark; Perry, George; Schmidt, Ann Marie; Stern, David; Häring, Hans Ulrich; Schleicher, Erwin; Nawroth, Peter P.

In: Diabetes, Vol. 50, No. 12, 01.01.2001, p. 2792-2808.

Research output: Contribution to journalArticle

Bierhaus, A, Schiekofer, S, Schwaninger, M, Andrassy, M, Humpert, PM, Chen, J, Hong, M, Luther, T, Henle, T, Klöting, I, Morcos, M, Hofmann, M, Tritschler, H, Weigle, B, Kasper, M, Smith, M, Perry, G, Schmidt, AM, Stern, D, Häring, HU, Schleicher, E & Nawroth, PP 2001, 'Diabetes-associated sustained activation of the transcription factor nuclear factor-κB', Diabetes, vol. 50, no. 12, pp. 2792-2808. https://doi.org/10.2337/diabetes.50.12.2792
Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. Diabetes. 2001 Jan 1;50(12):2792-2808. https://doi.org/10.2337/diabetes.50.12.2792
Bierhaus, Angelika ; Schiekofer, Stephan ; Schwaninger, Markus ; Andrassy, Martin ; Humpert, Per M. ; Chen, Jiang ; Hong, Mei ; Luther, Thomas ; Henle, Thomas ; Klöting, Ingrid ; Morcos, Michael ; Hofmann, Marion ; Tritschler, Hans ; Weigle, Bernd ; Kasper, Michael ; Smith, Mark ; Perry, George ; Schmidt, Ann Marie ; Stern, David ; Häring, Hans Ulrich ; Schleicher, Erwin ; Nawroth, Peter P. / Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. In: Diabetes. 2001 ; Vol. 50, No. 12. pp. 2792-2808.
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AU - Bierhaus, Angelika

AU - Schiekofer, Stephan

AU - Schwaninger, Markus

AU - Andrassy, Martin

AU - Humpert, Per M.

AU - Chen, Jiang

AU - Hong, Mei

AU - Luther, Thomas

AU - Henle, Thomas

AU - Klöting, Ingrid

AU - Morcos, Michael

AU - Hofmann, Marion

AU - Tritschler, Hans

AU - Weigle, Bernd

AU - Kasper, Michael

AU - Smith, Mark

AU - Perry, George

AU - Schmidt, Ann Marie

AU - Stern, David

AU - Häring, Hans Ulrich

AU - Schleicher, Erwin

AU - Nawroth, Peter P.

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N2 - Activation of the transcription factor nuclear factor-κB (NF-κB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-κB in vitro, we observed a long-lasting sustained activation of NF-κB in the absence of decreased IκBα in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-κBp65. A comparable increase in NF-κBp65 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-β peptide (Aβ) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-κB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a β-globin reporter transgene under control of NF-κB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-κB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-κB activation by ligands of RAGE was mediated by initial degradation of IκB proteins followed by new synthesis of NF-κBp65 mRNA and protein in the presence of newly synthesized IκBα and IκBβ. These data demonstrate that ligands of RAGE can induce sustained activation of NF-κB as a result of increased levels of de novo synthesized NF-κBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-κB activation observed in hyperglycemia and possibly other chronic diseases.

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