The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.

Chronic inflammatory bowel diseases (IBDs), specifically Crohn's disease (CD) and ulcerative colitis (UC), have increased significantly in western countries and Japan over the last decade, but very little is known about their pathogenesis. A candidate-gene approach recently identified NOD2/CARD15 as one susceptibility gene from the IBD1 locus on chromosome 16. Alterations in this gene were found in many Caucasian patients with CD; in particular, two nonsynonymous substitutions (R702W and G908R) and a frameshift mutation (1007fs) were shown to be independent risk factors for CD. We investigated DNA from 483 Japanese CD patients to detect those three mutations in NOD2/CARD15 by appropriate genotyping techniques, but found only an R702Q substitution in a single patient. Direct sequencing of DNA from 96 of our patients in the regions containing the three reported major mutations detected no sequence alterations of consequence. Our findings indicate that the NOD2/CARD15 gene is not a major contributor to CD susceptibility in the Japanese population.

In the development of novel therapeutic strategies for kidney disease, new renal biomarkers for early detection and accurate evaluation of renal injury are urgently required for both acute kidney injury (AKI) and chronic kidney disease (CKD). Fatty acid-binding protein 1 (FABP1) is expressed in renal proximal tubule cells and shed into urine in response to hypoxia caused by decreased peritubular capillary blood flow. To clarify the role of urinary FABP1 in kidney disease, we established human FABP1 transgenic mice and evaluated the responses of FABP1 to several AKI and CKD models. Moreover, there are accumulating clinical data that urinary FABP1 can detect human AKI earlier than serum creatinine and can distinguish the risk population for AKI. Investigation with "humanized" FABP1 transgenic mice and measurement of clinical samples allowed us to develop urinary FABP1 as a new renal biomarker. Further clinical studies are necessary to confirm the potential of urinary FABP1 for clinical application.

Objective-The goal of this study was to investigate the effects of stimulants for a nucleotide-binding domain, leucine-rich repeat-containing (NLR) protein family on human artery endothelial cells and murine arteries. Methods and Results-Human coronary artery endothelial cells were challenged in vitro with microbial components that stimulate NLRs or Toll-like receptors. We found stimulatory effects of NLR and Toll-like receptor ligands on the adhesion molecule expression and cytokine secretion by human coronary artery endothelial cells. On the basis of these results, we examined the in vivo effects of these ligands in mice. Among them, FK565, 1 of the nucleotide-binding oligomerization domain (Nod)-1 ligands induced strong site-specific inflammation in the aortic root. Furthermore, coronary arteritis/valvulitis developed after direct oral administration or ad libitum drinking of FK565. The degree of the respective vascular inflammation was associated with persistent high expression of proinflammatory chemokine/ cytokine and matrix metallopeptidase (Mmp) genes in each tissue in vivo by microarray analysis. Conclusion-This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1ligand. The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. These findings might lead to the clarification of the pathogenesis and pathophysiology of coronary artery disease in humans. Key Words: coronary artery disease Ⅲ immune system Ⅲ Kawasaki disease Ⅲ pathology Ⅲ coronary arteritis Ⅲ inflammation G erm-line encoded pattern-recognition receptors of the innate immune system sense exogenous microbial components and endogenous danger signals to protect the host. [1][2][3][4] The pattern-recognition receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors, the leucine-rich repeat-containing (NLR) protein family, and as-yet-unidentified pattern-recognition receptors that recognize double-stranded DNA. 1,3 The TLR, RIG-I-like receptor, and NLR families consist of 10 (human), 3, and more than 20 members, respectively. 1,3,4 In the cardiovascular system, endothelial cells are usually the first among the structural cells to sense microbial components through pattern-recognition receptors. Human endothelial cells express functional innate immune receptors, such as TLRs and NLRs. 5,6 There is a line of evidence that activation of TLRs, especially TLR4 and TLR2, contributes to the development and progression of cardiovascular diseases, including atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure. 7 With respect to NLRs, only a limited number of studies have shown that human endothelial cells express functional NLRs, nucleotide-binding oligomerization domain 1 (NOD1) and NOD2. Chlamydophila pneumoniae and Listeria monocytogenes elicited NOD1-dependent interleukin (IL)-8 production in endothelial cells. 8,9 A selective NOD1 ligand, FK565, ...