Objective-Atherosclerosis is considered to be a chronic inflammatory disease and many cytokines participate in the development of atherosclerosis. We focused on the role of interleukin-1␤ (IL-1␤), one of the proinflammatory cytokines secreted by monocytes/macrophages, in the progression of atherosclerosis. Methods and Results-We generated mice lacking both apoE and IL-1␤. The sizes of atherosclerotic lesions at the aortic sinus in apoEϪ/Ϫ/IL-1␤Ϫ/Ϫmice at 12 and 24 weeks of age showed a significant decrease of approximately 30% compared with apoEϪ/Ϫ/IL-1␤ ϩ/ϩ mice, and the percentage of the atherosclerotic area to total area of apoEϪ/Ϫ/IL-1␤Ϫ/Ϫ at 24 weeks of age also showed a significant decrease of about 30% compared with apoEϪ/Ϫ/IL-1␤ ϩ/ϩ . The mRNA levels of vascular cell adhesion molecule (VCAM)-1 and monocyte chemotactic protein-1 in the apoEϪ/Ϫ/ IL-1␤Ϫ/Ϫ aorta were significantly reduced compared with the apoEϪ/Ϫ/IL-1␤ ϩ/ϩ . Furthermore, VCAM-1 was also reduced at the protein level in apoEϪ/Ϫ/IL-1␤Ϫ/Ϫ aorta compared with apoEϪ/Ϫ/IL-1␤ ϩ/ϩ . Conclusions-The

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Marked increases in metabolites of the L-tryptophan-kynurenine pathway, L-kynurenine and quinolinic acid (Quin), were observed in serum and cerebrospinal fluid (CSF) of both the rat and human with renal insufficiency. The mechanisms responsible for their accumulation after renal insufficiency were investigated. In patients with chronic renal insufficiency, elevated levels of serum L-kynurenine and Quin were reduced by hemodialysis. In renal-insufficient rats, Quin and L-kynurenine levels in serum, brain, and CSF were also increased parallel to the severity of renal insufficiency. Urinary excretion of Quin (3.5-fold) and L-kynurenine (2.8-fold) was also increased. Liver L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels. Kynurenine 3-hydroxylase and quinolinic acid phosphoribosyltransferase were unchanged, but the activities of kynureninase, 3-hydroxyanthranilate dioxygenase, and aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) were significantly decreased. Systemic administrations of pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in control rats, demonstrating that changes in body ACMSDase activities in response to renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increased serum L-kynurenine concentrations are mainly due to the increased TDO and decreased kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after renal insufficiency. The accumulation of CSF L-kynurenine is caused by the entry of increased serum L-kynurenine, and the accumulation of CSF Quin is secondary to Quin from plasma and/or Quin precursor into the brain.