The composition of the glycosphingolipids of the human gastrointestinal tract was studied. The major neutral glycosphingolipids were ceramide monohexosides (e.g., GalCer, GlcCer), LacCer, Gb3Cer, Gb4Cer and more polar ones with more than four sugars, whereas neither Gg3Cer nor Gg4Cer were present. The acidic glycosphingolipids consisted of sulfatides and gangliosides such as GM3, GM1, GD3 and GD1a. Also a large amount of sulfatides was found in the gastric mucosa and duodenum. The concentrations of sulfatides in the fundic mucosa, antral mucosa and duodenum amounted to 416.0, 933.8 and 682.9 nmol/g of dry weight, respectively, exceeding those in the gastric mucosa and kidney of other mammals. The major molecular species of the sulfatides were identified as I3SO3-GalCer with hydroxylated longer-chain fatty acids based on the analyses by gas-liquid chromatography and negative ion fast-atom bombardment mass spectrometry. In contrast, gangliosides in these regions showed a tendency to be lower than sulfatides, and the molar ratios of sulfatides to gangliosides were about 2.0, whereas those in other parts were less than 0.5. A high content of sulfatides in the gastric and duodenal mucosa, where mucosa is easily insulted by acid, pepsin and bile salts, may be closely related to their roles in mucosal protection.

Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.

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To elucidate the genetic alterations that are specific to Thorotrast-induced liver cancers and their possible roles in tumorigenesis, we analyzed loss of heterozygosity (LOH) at 37 loci. Our previous study of liver cancers that were not associated with Thorotrast found LOH at 9 of these loci to be characteristic of intrahepatic cholangiocarcinoma (ICC), at 19 to be characteristic of hepatocellular carcinoma (HCC), and at 9 to be common to both ICC and HCC. LOH analysis was also performed in tissues of cholangiolocellular carcinoma, which is thought to originate from a common stem cell progenitor of hepatocytes and bile duct epithelial cells. We found frequent LOH at D4S1538, D16S2624 and D17S1303 to be common to all the subtypes of liver cancers, independent of the specific carcinogenic agent. In contrast, LOH at D4S1652 generally was not observed in Thorotrast-induced ICC. LOH analysis revealed that Thorotrast-induced ICC shares some LOH features with both ICC and HCC that were not induced by Thorotrast; however, it is more similar to ICC than to HCC in terms of genetic changes. This study could narrow down the crucial chromosomal loci whose deletions are relevant to hepatobiliary carcinogenesis irrespective of the carcinogenic agent. The study of LOH at loci other the those crucial ones may help us understand how the phenotype of liver cancers is determined.

Objectives Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b–C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms. Methods Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay. Results Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis. Conclusion Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc.