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

Jan Hn Lindeman (1) , Hazem Abdul-Hussien , Alexander Fm Schaapherder , J. Hajo van Bockel , Jan H von Der Thüsen , Dave L Roelen , Robert Kleemann

1 Department of Vascular Surgery

Inflammation plays a key-role in the pathogenesis of the abdominal aortic aneurysm (AAA). Yet, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is discussed controversially. Here, 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 biopsies with atherosclerotic wall biopsies taken from the same aortic region allowed us to identify AAA-specific inflammatory parameters that distinguish AAA from aortic atherosclerotic disease (ASD). RT-PCR, ELISA, Western blotting and immunohistochemistry were combined to assess cytokines and transcription factors on the mRNA and protein level, and their activation status. Compared to ASD, inflammatory parameters associated with Th1-type (T-bet, IL-2, IFN-γ, TNFα, IL-1α, T cytotoxic}-cells) and Th2-type responses (GATA3, IL-4, IL-10, IL-13, B-cells) were all elevated in AAA. Evaluation of major downstream inflammatory transcription factors revealed higher baseline levels of C/EBPα, β and δ in AAA. Baseline p65-NF-κB and c-jun (AP-1) levels were comparable, but their activated forms were strongly increased in AAA. Downstream target genes of p65-NF-κB and c-jun, IL-6 and IL-8, were hyperexpressed. Molecular and cellular processes associated with IL-6 and IL-8 hyperactivation were enhanced in AAA, i.e. the expression of p-STAT-3 and perforin was elevated, and the content of plasma cells, neutrophils and vasa vasorum was increased. Our findings demonstrate that AAA is a general inflammatory condition that 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, together clearly distinguishing AAA from ASD.

Mots clés: Medicine

Jan Hn Lindeman, Hazem Abdul-Hussien, Alexander Fm Schaapherder, J. Hajo van Bockel, Jan H von Der Thüsen, et al.. Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurismal from atherosclerotic aorta: IL-6 and IL-8 dominated inflammatory responses prevail in the human aneurysm. Clinical Science, 2007, 114 (11), pp.687-697. ⟨10.1042/CS20070352⟩. ⟨hal-00479405⟩