Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Export

@article{citeulike:282181, 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.}, address = {Department of Medicine I and Department of Neurology, University of Heidelberg, Heidelberg, Germany.}, author = {Bierhaus, A. and Schiekofer, S. and Schwaninger, M. and Andrassy, M. and Humpert, P. M. and Chen, J. and Hong, M. and Luther, T. and Henle, T. and Kl\"{o}ting, I. and Morcos, M. and Hofmann, M. and Tritschler, H. and Weigle, B. and Kasper, M. and Smith, M. and Perry, G. and Schmidt, A. M. and Stern, D. M. and H\"{a}ring, H. U. and Schleicher, E. and Nawroth, P. P.}, citeulike-article-id = {282181}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/11723063}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=11723063}, issn = {0012-1797}, journal = {Diabetes}, keywords = {diabetes, ikb, ikk, nfkb, type1diabetes}, month = {December}, number = {12}, pages = {2792--2808}, posted-at = {2005-08-15 11:34:50}, priority = {2}, title = {Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/11723063}, volume = {50}, year = {2001} }

TY - JOUR ID - citeulike:282181 L3 - citeulike-article-id:282181 N2 - 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. IS - 12 JF - Diabetes SN - 0012-1797 AD - Department of Medicine I and Department of Neurology, University of Heidelberg, Heidelberg, Germany. EP - 2808 TI - Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. VL - 50 SP - 2792 KW - diabetes KW - ikb KW - ikk KW - nfkb KW - type1diabetes AU - Bierhaus, A AU - Schiekofer, S AU - Schwaninger, M AU - Andrassy, M AU - Humpert, PM AU - Chen, J AU - Hong, M AU - Luther, T AU - Henle, T AU - Klöting, I AU - Morcos, M AU - Hofmann, M AU - Tritschler, H AU - Weigle, B AU - Kasper, M AU - Smith, M AU - Perry, G AU - Schmidt, AM AU - Stern, DM AU - Häring, HU AU - Schleicher, E AU - Nawroth, PP PY - 2001/12// UR - http://view.ncbi.nlm.nih.gov/pubmed/11723063 ER -