APRIL promotes proliferation, secretion and invasion of fibroblast-like synoviocyte from rats with adjuvant induced arthritis.

Fibroblast-like synoviocyte (FLS) is the ultimate effectual cells in the pathogenesis of rheumatoid arthritis (RA). The current study was undertaken to investigate whether a proliferation-inducing ligand (APRIL) mediates the function of FLS in an animal model of RA. Rat adjuvant-induced arthritis (AA) was induced by intradermal injection of 0.1 ml complete Freund's adjuvant. Synovium APRIL expression was detected by immunohistochemical analysis. The level of APRIL and matrix metalloproteinase (MMP)-9 were assayed by enzyme-linked immunosorbent assay. The expression of APRIL and its receptors (TACI, BCMA and BAFF-R) were assessed by immunofluorescence staining, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and real-time RT-PCR. The effects of APRIL on the function of FLS were investigated by MTT, Quantibody Rat Inflammation Array 1 and transwell assays, respectively. A higher concentration of APRIL was detected in AA synovium homogenate compared with normal group. AA FLS expressed APRIL, TACI, BAFF-R and BCMA at the mRNA levels, whereas only APRIL and BCMA were confirmed to be expressed on membrane by flow cytometry. APRIL stimulated AA FLS proliferation, migration and invasion and the secretion of proinflammatory factors. In addition, FLS cocultured with APRIL-treated B cells or T cells had a significantly greater proliferation than FLS cultured alone. Neutralization of APRIL by the TACI-Ig fusion protein attenuated these stimulating effects of APRIL on FLS. Our data indicate that APRIL may act as an important mediator for facilitating the function of FLS. Blockade of APRIL thus may be a valuable adjunct in the treatment of RA.

Chang Y ，Jia X ，Sun X ，Xu S ，Wu Y ，Zhang L ，Wei W ... -  《-》

Rheumatoid arthritis fibroblast-like synoviocytes express BCMA and are stimulated by APRIL.

Nagatani K ，Itoh K ，Nakajima K ，Kuroki H ，Katsuragawa Y ，Mochizuki M ，Aotsuka S ，Mimori A ... -  《-》

CP-25 attenuates the inflammatory response of fibroblast-like synoviocytes co-cultured with BAFF-activated CD4(+) T cells.

Total glucosides of paeony (TGP) is the first anti-inflammatory immune regulatory drug approved for the treatment of rheumatoid arthritis in China. A novel compound, paeoniflorin-6'-O-benzene sulfonate (code CP-25), comes from the structural modification of paeoniflorin (Pae), which is the effective active ingredient of TGP. The aim of the present study is to investigate the effect of CP-25 on adjuvant arthritis (AA) fibroblast-like synoviocytes (FLS) co-cultured with BAFF-activated CD4(+) T cells and the expression of BAFF-R in CD4(+) T cells. The mRNA expression of BAFF and its receptors was assessed by qPCR. The expression of BAFF receptors in CD4(+) T cells was analyzed by flow cytometry. The effect of CP-25 on AA rats was evaluated by their joint histopathology. The cell culture growth of thymocytes and FLS was detected by cell counting kit (CCK-8). The concentrations of IL-1β, TNF-α, and IL-6 were measured by Enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of BAFF and BAFF-R were enhanced in the mesenteric lymph nodes of AA rats, TACI expression was reduced, and BCMA had no change. The expression of BAFF-R in CD4(+) T cells was also enhanced. CP-25 alleviated the joint histopathology and decreased the expression of BAFF-R in CD4(+) T cells from AA rats in vivo. In vitro, CP-25 inhibited the abnormal cell culture growth of BAFF-stimulated thymocytes and FLS. In the co-culture system, IL-1β, IL-6 and TNF-α production was enhanced by FLS co-cultured with BAFF-activated CD4(+) T cells. Moreover, BAFF-stimulated CD4(+) T cells promoted the cell culture growth of FLS. The addition of CP-25 decreased the expression of BAFF-R in CD4(+) T cells and inhibited the cell culture growth and cytokine secretion ability of FLS co-cultured with BAFF-activated CD4(+) T cells. The present study indicates that CP-25 may repress the cell culture growth and cytokine secretion ability of FLS, and its inhibitory effects might be associated with its ability to inhibit the expression of BAFF-R in CD4(+) T cells in a co-culture. These observations might provide a scientific basis for the development of new drugs for the treatment of autoimmune diseases by CP-25.

Jia X ，Wei F ，Sun X ，Chang Y ，Xu S ，Yang X ，Wang C ，Wei W ... -  《-》

APRIL and BAFF proteins increase proliferation of human adipose-derived stem cells through activation of Erk1/2 MAP kinase.

Zonca M ，Mancheño-Corvo P ，DelaRosa O ，Mañes S ，Büscher D ，Lombardo E ，Planelles L ... -  《-》

Expression and effects of B-lymphocyte stimulator and its receptors in T cell-mediated autoimmune arthritis.

The objective of this study was to determine the expression and effects of B-lymphocyte stimulator (BLyS) in T cell-mediated autoimmune arthritis, a rat model of human rheumatoid arthritis (RA). Rat adjuvant-induced arthritis (AA) was induced by intradermal injection of 0.1ml complete Freund's adjuvant. Arthritis was evaluated by the histopathological examination of joint ankle. The BLyS expression was detected by immunohistochemical analysis. The level of BLyS and interleukin (IL)-17 were assayed by enzyme-linked immunosorbent assay. The gene expression of BLyS and its receptors (TACI, BCMA and BAFF-R) were assessed by quantitative reverse-transcription polymerase chain reaction. The effect of BLyS on the function of T cell was investigated by transwell assay. Using an AA rat model, we detected dysregulated expression and level of BLyS and its receptors in the local joint synovium tissue, peripheral lymphoid organs (spleen) and immune cells (macrophage, dendritic cells (DC) and T cell) at the peak of inflammation. In vitro, BLyS-treated DC induced IL-17 producing T cells. Neutralization of BLyS by the TACI-Ig fusion protein attenuated these stimulating effects of BLyS. These data suggest that the overproduction of BLyS may contribute to T cell responses and may be an attractive target for control of autoimmune diseases, such as RA, that involves both T and B cells.

Chang Y ，Sun X ，Jia X ，Xu S ，Wei F ，Yang X ，Wei W ... -  《-》