IL-6: A Janus-like factor in abdominal aortic aneurysm disease.
An abdominal aortic aneurysm (AAA) is part of the atherosclerotic spectrum of diseases. The disease is hallmarked by a comprehensive localized inflammatory response with striking IL-6 hyperexpression. IL-6 is a multifaceted cytokine that, depending on the context, acts as a pro- or anti-inflammatory factor. In this study, we explore a putative role for IL-6 in AAA disease.



ELISA's, Western blot analysis, real time PCR and array analysis were used to investigate IL-6 expression and signaling in aneurysm wall samples from patients undergoing elective AAA repair. A role for IL-6 in AAA disease was tested through IL-6 neutralization experiments (neutralizing antibody) in the elastase model of AAA disease.



We confirmed an extreme disparity in aortic wall IL-6 content between AAA and atherosclerotic disease (median [5th-95th percentile] aortic wall IL-6 content: 281.6 [0.0-1820.8] (AAA) vs. 1.9 [0.0-37.8] μg/g protein (atherosclerotic aorta), (p < 0.001). Array analysis followed by pathway analysis showed that IL-6 hyper-expression is followed by increased IL-6 signaling (p < 0.000039), an observation confirmed by higher aneurysm wall pSTAT3 levels, and SOCS1 and SOCS3 mRNA expression, (p < 0.018). Remarkably, preventive IL-6 neutralization i.e. treatment started one day prior to the elastase-induction resulted in >40% 7-day mortality due to aortic rupture. In contrast, delayed IL-6 neutralization (i.e. neutralization started at day 4 after elastase induction) did not result in ruptures, and quenched AAA growth (p < 0.021).



AAA disease is characterized by increased IL-6 signaling. In the context of the elastase model of AAA disease, IL-6 appears a multi-faceted factor, protective upon acute injury, but negatively involved in the perpetuation of the disease process.
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Vivianne B C
VBC
Kokje
Department of Vascular and Endovascular Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
Gabor
G
Gäbel
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
Dave
D
Koole
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Bernd H
BH
Northoff
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Lesca M
LM
Holdt
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Jaap F
JF
Hamming
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: Lindeman@lumc.nl.
Jan H N
JHN
Lindeman
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics*; D001019:Aortic Rupture; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010196:Pancreatic Elastase / Q000378:metabolism; D015398:Signal Transduction
D015850:Interleukin-6; C577686:interleukin-6, mouse; D010196:Pancreatic Elastase
Abdominal aortic aneurysm; Elastase model; IL-6; Inflammation; Rupture