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  • 1
    Keywords: NF-KAPPA-B ; IMMUNE-RESPONSES ; GLYCATION END-PRODUCTS ; CENTRAL-NERVOUS-SYSTEM ; CELL-ADHESION MOLECULE ; TOLL-LIKE RECEPTORS ; RHEUMATOID-ARTHRITIS ; SUSTAINED INTESTINAL INFLAMMATION ; NITRIC-OXIDE PRODUCTION ; PATTERN MOLECULES
    Abstract: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p 〈 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-kappaB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-kappaB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p 〈 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
    Type of Publication: Journal article published
    PubMed ID: 23729438
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  • 2
    Abstract: BACKGROUND & AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) functions analogue to the receptor of advanced glycation end products, which has been implicated in the development of diabetic nephropathy (DN). We investigated the expression of ALCAM and its ligand S100B in patients with DN. METHODS: A total of 34 non-diabetic patients, 29 patients with type 2 diabetes and normal albuminuria and 107 patients with type 2 diabetes complicated with DN were assessed for serum concentration of soluble ALCAM (sALCAM) by ELISA. Expression of ALCAM and S100B in kidney histology from patients with DN was determined by immunohistochemistry. Cell expression of ALCAM and S100B was analyzed through confocal immunofluorescence microscopy. RESULTS: Serum concentration of sALCAM was increased in diabetic patients with DN compared to non-diabetic (59.85+/-14.99ng/ml vs. 126.88+/-66.45ng/ml, P〈0.0001). Moreover sALCAM correlated positively with HbA1c (R=0.31, P〈0.0001), as well as with the stages of chronic kidney disease and negatively correlated with eGFR (R=-0.20, P〈0.05). In diabetic patients with normal albuminuria sALCAM was increased compared to patients with DN (126.88+/-66.45ng/ml vs. 197.50+/-37.17ng/ml, P〈0.0001). In diabetic patients, ALCAM expression was significantly upregulated in both the glomeruli and tubules (P〈0.001). ALCAM expression in the glomeruli correlated with presence of sclerosis (R=0.25, P〈0.001) and localized mainly in the podocytes supporting the hypothesis that membrane bound ALCAM drives diabetic nephropathy and thus explaining sALCAM decrease in diabetic patients with DN. The expression of S100B was increased significantly in the glomeruli of diabetic patients (P〈0.001), but not in the tubules. S100B was as well localized in the podocytes. CONCLUSIONS: This study identifies for the first time ALCAM as a potential mediator in the late complications of diabetes in the kidney.
    Type of Publication: Journal article published
    PubMed ID: 28325697
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