Fucosyltransferase 1 mediates angiogenesis, cell adhesion and rheumatoid arthritis synovial tissue fibroblast proliferation

Abstract

IntroductionWe previously reported that sialyl Lewisy, synthesized by fucosyltransferases, is involved in angiogenesis. Fucosyltransferase 1 (fut1) is an α(1,2)-fucosyltransferase responsible for synthesis of the H blood group and Lewisy antigens. However, the angiogenic involvement of fut 1 in the pathogenesis of rheumatoid arthritis synovial tissue (RA ST) has not been clearly defined.MethodsAssay of α(1,2)-linked fucosylated proteins in RA was performed by enzyme-linked lectin assay. Fut1 expression was determined in RA ST samples by immunohistological staining. We performed angiogenic Matrigel assays using a co-culture system of human dermal microvascular endothelial cells (HMVECs) and fut1 small interfering RNA (siRNA) transfected RA synovial fibroblasts. To determine if fut1 played a role in leukocyte retention and cell proliferation in the RA synovium, myeloid THP-1 cell adhesion assays and fut1 siRNA transfected RA synovial fibroblast proliferation assays were performed.ResultsTotal α(1,2)-linked fucosylated proteins in RA ST were significantly higher compared to normal (NL) ST. Fut1 expression on RA ST lining cells positively correlated with ST inflammation. HMVECs from a co-culture system with fut1 siRNA transfected RA synovial fibroblasts exhibited decreased endothelial cell tube formation compared to control siRNA transfected RA synovial fibroblasts. Fut1 siRNA also inhibited myeloid THP-1 adhesion to RA synovial fibroblasts and RA synovial fibroblast proliferation.ConclusionsThese data show that α(1,2)-linked fucosylated proteins are upregulated in RA ST compared to NL ST. We also show that fut1 in RA synovial fibroblasts is important in angiogenesis, leukocyte-synovial fibroblast adhesion, and synovial fibroblast proliferation, all key processes in the pathogenesis of RA.

A key role for Fut1-regulated angiogenesis and ICAM-1 expression in K/BxN arthritis

“…For instance, cytokine expression and MN ingress are two key factors which contribute to the progression of RA and inflammatory arthritis 36–38. We have data showing that MCP-1/CCL2 expression is decreased in RA ST fibroblasts39 and human monocytes (data not shown) when Fut1 is deficient and monocytes migrate less in the absence of Fut1, suggesting the importance and the mechanism by which Fut1 is involved in the development of K/BxN arthritis.…”

The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation

“…In mammary gland, 2′-FL is synthesised through enzymatic transfer of fucose from guanosine 5′-diphosphate-l-fucose to lactose by FUT2 52. The resulting α-1,2-linked fucosyllactose, 2′-FL,53 is the predominant oligosaccharide in the milk of secretors, representing up to 30% of total HMOSs 54 55.…”

MicroRNA-101-3p inhibits fibroblast-like synoviocyte proliferation and inflammation in rheumatoid arthritis by targeting PTGS2

“…Approximately 2 volumes of 1 mg/ml collagenase I (Gibco, U.S.A.) was added to digest the synovial membrane in a 37 • C incubator for 2 h. After the detachment, the synovial membrane was filtered through a nylon mesh of 70 μm pore size, centrifuged, and rinsed with PBS. The cells were resuspended in DMEM containing 10% FBS, and the medium was refreshed the next day [21] to obtain FLSs in RA (RA-FLSs). The morphology of the fibroblasts was observed.…”