Abstract
Although the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear, evidence is accumulating to support a central role for inflammation. Inflammatory responses are coordinated by various soluble cytokines of which IL-6 is one of the major proinflammatory cytokines. In this study we examined the role of IL-6 in the pathogenesis of experimental AAA induced by a periaortic exposure to CaCl2 in mice. We now report that the administration of MR16-1, a neutralizing monoclonal antibody specific for the mouse IL-6 receptor, mildly suppressed the development of AAA. The inhibition of IL-6 signaling provoked by MR16-1 also resulted in a suppression of Stat3 activity. Conversely, no significant changes in either NFκB activity, Jnk activity or the expression of matrix metalloproteinases (Mmp) -2 and -9 were identified. Transcriptome analyses revealed that MR16-1-sensitive genes encode chemokines and their receptors, as well as factors that regulate vascular permeability and cell migration. Imaging cytometric analyses then consistently demonstrated reduced cellular infiltration for MR16-1-treated AAA. These results suggest that IL-6 plays an important but limited role in AAA pathogenesis, and primarily regulates cell migration and infiltration. These data would also suggest that IL-6 activity may play an important role in scenarios of continuous cellular infiltration, possibly including human AAA.
Highlights
Abdominal aortic aorta (AAA) is a local expansion of the aortic diameter due to a weakened aortic wall [1]
As we observed infiltration of monocytes/macrophages in AAA tissue, we examined the expression of monocyte chemoattractant protein-1 (Mcp-1) that has been reported to participate in AAA pathogenesis [19, 20] by immunohistochemistry (Fig 3A)
Because calcification is a common feature of the CaCl2-induced AAA model and human AAA [4], and IL-6 may be causally related to vascular calcification [21], we evaluated the effect of MR16-1 on the extent of aortic wall calcification (Fig 3B)
Summary
Abdominal aortic aorta (AAA) is a local expansion of the aortic diameter due to a weakened aortic wall [1]. The absence of a precise mechanism for this pathology has hampered the development of effective therapeutic strategies. Recent studies have highlighted the importance of tissue destructive inflammation in AAA pathogenesis [2,3,4]. We and others have demonstrated that pharmacologic intervention against mediators of pro-inflammatory signaling, including c-Jun N-terminal kinase (Jnk) [5] and nuclear factor kappa B (NFκB) [6] are effective in suppressing tissue destruction in a mouse model of AAA. There is an accumulating body of evidence to support the idea that regulating inflammation is a promising strategy with which to control the progression of AAA [7]
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