title: Deficiency of interleukin-1 receptor antagonist promotes spontaneous femoral artery aneurysm formation in mice.
abstract: Femoral artery aneurysms (FAAs) are very rare, and their natural history is not well understood. In this study, we sought to analyze the pathogenesis of inflammatory FAAs in interleukin-1 receptor antagonist-deficient (IL-1Ra(-/-)) B6 mice. Systolic arterial pressures and plasma lipid levels of IL-1Ra(-/-) mice and wild-type (WT) mice did not differ significantly. However, IL-1Ra(-/-) mice spontaneously developed fusiform FAAs. Real-time PCR of 9-month-old IL-1Ra(-/-) mice revealed significantly increased mRNA levels of IL-1β (6.6-fold), tumor necrosis factor-α (TNF-α) (12.4-fold), and matrix metalloproteinase-9 (6.0-fold) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the FAAs in IL-1Ra(-/-) mice, and elastin staining showed destruction of both the internal and external elastic lamina in IL-1Ra(-/-) mice. Afterward, macrophage function was studied. After lipopolysaccharide (1 μg/mL) stimulation, IL-1Ra-deficient macrophages produced much higher levels of TNF-α than those from WT mice. Finally, we performed bone marrow cell transplantation. FAAs with many inflammatory cells in the adventitia were detected in several WT mice that received bone marrow cells from IL-1Ra(-/-) mice (44%), but not from WT mice (0%). Our study is the first to demonstrate that IL-1Ra deficiency in inflammatory cells disrupts immune system homeostasis and induces inflammatory FAAs in IL-1Ra(-/-) B6 mice. We believe that these mice will provide much information about the natural history and management of FAAs.
authors.affiliation: Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan. Electronic address: isoda@ndmc.ac.jp.
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.affiliation: Department of Medical Engineering, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kitagaki
authors.affiliation: Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Tomiharu
authors.initials: T
authors.lastname: Niida
authors.affiliation: Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsubara
authors.affiliation: Department of Medical Engineering, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
authors.affiliation: Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
mesh_terms: D000783:Aneurysm / Q000209:etiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005263:Femoral Artery; D056660:Hereditary Autoinflammatory Diseases / Q000150:complications*; D053590:Interleukin 1 Receptor Antagonist Protein; D008213:Lymphocyte Activation / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D018925:Chemokines; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger