Makiko Hayashi

The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice

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.

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm

Background Abdominal aortic aneurysm (AAA) is a potentially life‐threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. Methods and Results We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B‐cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B‐cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B‐cell–deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase‐9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin‐6 and metalloproteinase‐9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. Conclusions From these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue‐destructive activities. Finally, we identified Syk as a potential therapeutic target.

Miliary Tuberculosis Noticed by the Efficacy of Levofloxacin Monotherapy

1 Department of Infection Control and Prevention, Kurume University School of Medicine 2 Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine 3 Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine 4 Coronary Care Unit, Advanced Emergency Medical Service Center, Kurume University School of Medicine 5 Department of Pathology, Kurume University School of Medicine