title: Sulfoglucuronosyl paragloboside is a ligand for T cell adhesion: regulation of sulfoglucuronosyl paragloboside expression via nuclear factor kappaB signaling.
abstract: Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta stimulate glucuronosyltransferase genes (S and P) in endothelial cells (ECs) and up-regulate sulfoglucuronosyl paragloboside (SGPG) expression, which serves as a ligand for T cell adhesion. However, the mechanism of cytokine-mediated gene up-regulation has not been elucidated. To evaluate the precise mechanism of SGPG up-regulation, we have specifically inhibited the SGPG synthesis in the cerebromicrovascular EC line (SV-HCECs), a transformed brain ECs of human origin. SV-HCECs were transfected with small interfering RNA designed to mimic the human natural killer epitope-1 sulfotransferase (HNK-1ST), the ultimate enzyme that transfers the sulfate group to glucuronic acid for SGPG synthesis. An inhibition of SGPG expression along with a reduction of human CD4(+) cell adhesion was observed in siRNA HNK-1ST (siHNK-1)-transfected cells after TNFalpha stimulation. A thorough screening of the signaling system confirmed that TNFalpha/IL-1beta stimulation up-regulated nuclear factor kappaB (NFkappaB) signaling in SV-HCECs. siHNK-1 transfection interfered with the SGPG up-regulation after TNFalpha/IL-1beta stimulation in transfected cells and reduced the T cell adhesion. Hence, our study indicates that T cell-SGPG adhesion in SV-HCECs may proceed through NFkappaB activation. In addition, siHNK-1 transfection reduced the NFkappaB activity compared with cells that were transfected with scrambled siRNA, before and after TNFalpha/IL-1beta stimulation. This is the first report indicating that NFkappaB signaling is involved in SGPG gene expression in brain ECs by an unknown mechanism. Its down-regulation by inhibiting HNK-1ST expression may have a potential use in preventing the T cell invasion and consequently nerve damage during inflammation.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Somsankar
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Jeane
authors.initials: J
authors.lastname: Silva
authors.forename: Guanghu
authors.initials: G
authors.lastname: Wang
authors.forename: Robert K
authors.initials: RK
authors.lastname: Yu
mesh_terms: D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015704:CD4 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005915:Globosides / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015238:Sulfotransferases / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000097811:Carbohydrate Sulfotransferases
chemical_list: D015704:CD4 Antigens; D005915:Globosides; D053583:Interleukin-1beta; D016328:NF-kappa B; D034741:RNA, Small Interfering; D015238:Sulfotransferases; D014409:Tumor Necrosis Factor-alpha; C051917:sulfate-3-glucuronyl paragloboside; C499549:CHST10 protein, human; D000097811:Carbohydrate Sulfotransferases