Enhancement of lymphocyte migration and cytokine production by ephrinB1 system in rheumatoid arthritis

Abstract

Although the etiology of early events in rheumatoid arthritis (RA) remains undefined, an anomaly in T cell homeostasis and hyperproliferation of synovial-lining cells are involved in the disease process. Since it has been reported that the ephrin/Eph receptor system plays important signaling roles in inflammation processes, we attempted to examine ephrinB molecules in T cells and synovial cells derived from RA in this study. The expression level of ephrinB1 was significantly high in synovial fibroblasts and CD3-positive exudate lymphocytes in synovial tissues derived from patients with RA compared with those in osteoarthritis (OA). Protein and mRNA levels of ephrinB1 were also higher in peripheral blood lymphocytes (PBLs) prepared from patients with RA than those from normal controls. Similar results were obtained from an animal model of human RA, collagen antibody-induced arthritis mice. Moreover, a recombinant ephrinB1/Fc fusion protein stimulated normal PBLs to exhibit enhanced migration and production of TNF-alpha. EphrinB1/Fc also activated synovial cells established from patients with RA to produce IL-6. Tyrosine phosphorylation of EphB1 was induced in these cells by ephrinB1/Fc. The CpG islands in the 5' upstream regulatory region of the ephrinB1 gene were hypomethylated in RA patients compared with those of normal donors. These results suggest that ephrinB1 and EphB1 receptors play an important role in the inflammatory states of RA, especially by affecting the population and function of T cells. Inhibition of the ephrinB/EphB system might be a novel target for the treatment of RA.

Epigenome Analysis Reveals TBX5 as a Novel Transcription Factor Involved in the Activation of Rheumatoid Arthritis Synovial Fibroblasts

“…These studies showed that DNA methylation can play an important role in various pathways, such as apoptosis and IL-6, CXCL12, and Ephrin-B1 expression in RASF (20)(21)(22). These results prompted us to perform a genome-wide DNA methylation analysis.…”

Regulation of immune cell responses by semaphorins and their receptors

“…1 For example, some axon guidance molecules, such as slits [2][3][4] and ephrins, [5][6][7][8] have been shown to regulate immune cell migration. In addition, T-cell-antigenpresenting cell contact sites, the so-called 'immunological synapse', is structurally similar to the 'neurological synapse' that connects pairs of neurons.…”

Inflammatory memories: Is epigenetics the missing link to persistent stromal cell activation in rheumatoid arthritis?

“…Interestingly, also in PBMCs and T cells from RA patients disturbances of DNA methylation could be detected [39]. Particularly, in RA PBMCs loss of methylation in the promoter of the IL-6 and the ephrinB1 gene was found to be connected to increased expression of these genes in RA [40,41].…”