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Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm

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Author: Lindeman, J.H.N. · Abdul-Hussien, H. · Schaapherder, A.F.M. · Bockel, J.H. van · Thüsen, J.H. vonder · Roelen, D.L. · Kleemann, R.
Type:article
Date:2008
Source:Clinical Science, 11-12, 114, 687-697
Identifier: 240842
doi: doi:/10.1042/CS20070352
Keywords: Health · Abdominal aortic aneurysm · Atherosclerosis · Inflammation · Interleukin · Transcription factor · CCAAT enhancer binding protein alpha · CCAAT enhancer binding protein beta · CCAAT enhancer binding protein delta · Cytokine · Gamma interferon · Interleukin 10 · Interleukin 13 · Interleukin 1alpha · Interleukin 2 · Interleukin 4 · Interleukin 6 · Interleukin 8 · Messenger RNA · Perforin · STAT3 protein · transcription factor · transcription factor AP 1 · transcription factor GATA 3 · transcription factor RelA · transcription factor T bet · tumor necrosis factor alpha · autacoid · biological marker · abdominal aorta aneurysm · adult · aged · aorta atherosclerosis · aorta wall · B lymphocyte · Cellular immunity · Clinical article · Controlled study · Cytotoxic T lymphocyte · Enzyme linked immunosorbent assay · Female · Human · Human tissue · Immunohistochemistry · Male · Medical parameters · Neutrophil · Plasma cell · Protein expression · Real time polymerase chain reaction · Th1 cell · Th2 cell · Vasa vasorum · Western blotting · Aorta valve stenosis · Biosynthesis · Differential diagnosis · Genetics · Immunology · Metabolism · Methodology · Physiology · Reverse transcription polymerase chain reaction · Aged · Aortic Aneurysm, Abdominal · Aortic Valve Stenosis · Atherosclerosis · Biological Markers · Diagnosis, Differential · Female · Gene Expression Profiling · Humans · Inflammation Mediators · Male · Middle Aged · Reverse Transcriptase Polymerase Chain Reaction · Th1 Cells · Th2 Cells · Transcription Factors

Abstract

Inflammation plays a key role in the pathogenesis of an AAA (abdominal aortic aneurysm); however, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is controversial. In the present study, we set out to determine the aortic levels of inflammatory cytokines in relation to downstream inflammatory transcription factors and cellular responses. A comparison of AAA wall samples with atherosclerotic wall samples taken from the same aortic region allowed AAA-specific inflammatory parameters to be identified that distinguish AAAs from ASD (aortic atherosclerotic disease). RT-PCR (real-time PCR), ELISA, Western blotting and immunohistochemistry were combined to assess cytokines and transcription factors at the mRNA and protein level, and their activation status. Compared with ASD, inflammatory parameters associated with Th1-type [T-bet, IL (interleukin)-2, IFN-γ (interferon-γ), TNF-α (tumour necrosis factor-α), IL-1α and cytotoxic T-cells] and Th2-type [GATA3, IL-4, IL-10, IL-13 and B-cells] responses were all increased in AAA samples. Evaluation of major downstream inflammatory transcription factors revealed higher baseline levels of C/EBP (CCAAT/enhancer-binding protein) α;, β and δ in the AAA samples. Baseline p65 NF-κB (nuclear factor κB) and c-Jun [AP-1 (activator protein-1)] levels were comparable, but their activated forms were strongly increased in the AAA samples. Downstream target genes of p65 NF-κB, c-Jun, IL-6 and IL-8 were hyperexpressed. Molecular and cellular processes associated with IL-6 and IL-8 hyperactivation were enhanced in the AAA samples, i.e. the expression of phospho-STAT-3 (signal transducer and activator of transcription-3) and perforin were elevated, and the content of plasma cells, neutrophils and vasa vasorum was increased. In conclusion, our findings demonstrate that an AAA is a general inflammatory condition which is characterized by enhanced expression and activation of pro-inflammatory transcription factors, accompanied by IL-6 and IL-8 hyperexpression and exaggerated downstream cellular responses, which together clearly distinguish an AAA from ASD. © The Authors. Chemicals / CAS: gamma interferon, 82115-62-6; interleukin 13, 148157-34-0; interleukin 2, 85898-30-2; interleukin 8, 114308-91-7; perforin, 119332-27-3; transcription factor GATA 3, 137878-55-8; Biological Markers; Inflammation Mediators; Interleukin-6; Interleukin-8; Transcription Factors