Clinical Science (2008) 114, 687–697 - J.H.N. Lindeman and others - Pro-inflammatory transcription factors in abdominal aortic aneurysms

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Clinical Science (2008) 114, (687–697) (Printed in Great Britain)

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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

Jan H. N. LINDEMAN*, Hazem ABDUL-HUSSIEN*, Alexander F. M. SCHAAPHERDER*, J. Hajo VAN BOCKEL*, Jan H. VON DER THÜSEN†, Dave L. ROELEN‡ and Robert KLEEMANN§

*Department of Vascular and Transplantation Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands, †Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands, ‡Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands, and §Department of Vascular and Metabolic Diseases, TNO-Quality of Life, 2301 CE Leiden, The Netherlands

Key words: abdominal aortic aneurysm, atherosclerosis, cytokine, inflammation, interleukin, transcription factor.

Abbreviations: AAA, abdominal aortic aneurysm; AP-1, activator protein-1; ASD, aortic atherosclerotic disease; C/EBP, CCAAT/enhancer-binding protein; CI, confidence interval; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte/macrophage colony-stimulating factor; IFN-γ, interferon-γ; IHC, immunohistochemical; IL, interleukin; IL-6R, IL-6 receptor; MCP-1, monocyte chemoattractant protein-1; MIF, migration inhibitory factor; MIP-1β, macrophage inflammatory protein-1β; MMP, matrix metalloproteinase; MPO, myeloperoxidase; NF-κB, nuclear factor κB; RT-PCR, real-time PCR; sIL-6R, soluble IL-6R; STAT-3, signal transducer and activator of transcription-3; TNF-α, tumour necrosis factor-α.

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.