Enhancement of lymphocyte migration and cytokine production by ephrinB1 system in rheumatoid arthritis.
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.
Kitamura
Takuya
T
Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan.
Kabuyama
Yukihito
Y
Kamataki
Akihisa
A
Homma
Miwako K
MK
Kobayashi
Hideo
H
Aota
Shigeo
S
Kikuchi
Shin-ichi
S
Homma
Yoshimi
Y
D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000032:analysis; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D017252:CD3 Complex; D016207:Cytokines; C484288:EFNB1 protein, human; C092571:Efnb1 protein, mouse; D036387:Ephrin-B1; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine