Transcription factor NF-kappa B is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-alpha or interleukin-1 beta.
Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta up-regulate type 1 angiotensin II receptor (AT(1)) mRNA and protein in cultured neonatal rat cardiac fibroblasts. The use of pharmacologic inhibitors and a degradation-resistant mutant I kappa B-alpha demonstrated that the transcription factor nuclear factor-kappa B (NF-kappa B) is necessary for cytokine-induced AT(1) up-regulation. The increase in AT(1) mRNA with TNF-alpha treatment is slow, reaching significance by 6-12 h and peaking by 24-48 h. Electrophoretic mobility shift assays revealed that NF-kappa B nuclear translocation was maintained for > or = 24 h with a single dose of TNF-alpha. Since prolonged NF-kappa B activation appeared necessary to maximize AT(1) up-regulation, the mechanism of persistent NF-kappa B activation was studied further. Stimulation with TNF-alpha induced a >10x increase in I kappa B kinase (IKK) activity that quickly diminished by 20 min. I kappa B-alpha and I kappa B-beta proteins were degraded during this time, and I kappa B-alpha was resynthesized subsequently by NF-kappa B-dependent transcription. However, I kappa B isoforms and IKK activity did not return completely to unstimulated values during a 12-h time course. These results suggest that low but persistent IKK activity and I kappa B degradation lead to prolonged NF-kappa B nuclear translocation and maximal AT(1) up-regulation in the continued presence of TNF-alpha.
Cowling
Randy T
RT
Department of Medicine, Division of Cardiology, University of California, San Diego Medical Center, San Diego, California 92103-8411, USA.
Gurantz
Devorah
D
Peng
JianFeng
J
Dillmann
Wolfgang H
WH
Greenberg
Barry H
BH
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D020033:Protein Isoforms; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D016211:Transforming Growth Factor alpha; D000072000:NF-KappaB Inhibitor alpha