Objective. Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P 1 signaling in the pathogenesis of rheumatoid arthritis (RA).Methods. We examined S1P 1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P 1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor ␣ (TNF␣)-or interleukin

Summary. Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme‐linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0·31 ng/ml and 0·08 ng/ml respectively, P < 0·01; HGF: mean 2·17 ng/ml and 0·45 ng/ml, respectively, P < 0·001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M‐protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0·05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0·01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0·01, P < 0·05, P < 0·05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0·01, P = 0·02, respectively, log‐rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.

Primary Sjögren’s syndrome (SS) is an autoimmune disease characterized by inflammatory mononuclear cell infiltration and destruction of epithelial cells of lacrimal and salivary glands. Sphingosine 1-phosphate (S1P) and signaling through its receptor S1P1 have been implicated in many critical cellular events including inflammation, cancer, and angiogenesis. This study was undertaken to examine the role of S1P1 signaling in the pathogenesis of primary SS. S1P1 and sphingosine kinase 1, which converts sphingosine to S1P, were detected in the cytoplasm of inflammatory mononuclear cells, vascular endothelial cells, and epithelial cells in all labial salivary glands by immunohistochemistry. The expression of S1P1 in inflammatory mononuclear cells was enhanced in advanced stages of primary SS. S1P enhanced proliferation and IFN-γ production by CD4+ T cells. The enhancing effect of S1P on IFN-γ production by CD4+ T cells was stronger in patients with primary SS than in healthy controls. S1P also enhanced Fas expression and Fas-mediated caspase-3 induction in salivary gland epithelial cells. IL-6 expression was detected in the cytoplasm of inflammatory mononuclear cells and ductal epithelial cells and was enhanced in advanced stages of primary SS. Furthermore, both IFN-γ and S1P augmented IL-6 secretion by salivary gland epithelial cells. These effects of S1P were inhibited by pretreatment of pertussis toxin. Our data reveal that S1P1 signaling may modulate the autoimmune phenotype of primary SS by the action of immune as well as epithelial cells.

The salivary flow rate and EGF levels are decreased in SS, and this deterioration in saliva quality causes refractory intraoral manifestations. Our findings have provided new therapeutic targets for SS.

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Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-κB ligand (RANKL) in RA synoviocytes and CD4+ T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4+ T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4+ T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-α in MH7A cells and CD4+ T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4+ T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.

Summary. In this study, we examined osteopontin (OPN) production in myeloma cells and plasma OPN levels in multiple myeloma (MM) patients. We assessed OPN production in bone marrow cells (BMCs) by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA). We also assessed OPN production in various B-cell malignant cell lines, including three myeloma cell lines by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. In addition, we measured plasma OPN concentrations by ELISA in 30 MM patients, 21 monoclonal gammopathy of undetermined significance (MGUS) patients and 30 healthy volunteers. As a result, in an immunocytochemical study, abundant OPN was detected in BMCs from overt MM patients, whereas no OPN was detected in BMCs from patients with other haematological diseases, including MGUS. Cultured BMCs from overt MM patients produced more OPN than those from patients with either smouldering MM or MGUS. Myeloma cell lines spontaneously produced OPN. Plasma OPN levels of MM patients were significantly higher than those of MGUS patients and healthy volunteers (P < 0AE05). Moreover, they correlated with both progression and bone destruction of the disease (P < 0AE05). These suggest that myeloma cells actively produce OPN, which possibly contributes to osteoclastic bone resorption in MM. Plasma OPN levels may be a useful biomarker for assessing bone destruction in MM and distinguishing MM from MGUS or smouldering MM.

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