LIGHT up-regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytes.
OBJECTIVE
To study the expression of LIGHT (tumor necrosis factor superfamily 14) and herpesvirus entry mediator (HVEM; tumor necrosis factor receptor superfamily 14) in rheumatoid arthritis (RA) and to determine the regulatory role of LIGHT on the effector functions of fibroblast-like synoviocytes (FLS).


METHODS
The expression of LIGHT and HVEM was assessed by immunohistochemical staining of synovial tissue and by flow cytometric analysis of mononuclear cells. The presence of HVEM and lymphotoxin beta receptor was measured by reverse transcriptase-polymerase chain reaction and by flow cytometry. The regulation of effector molecules, including matrix metalloproteinases (MMPs) and adhesion molecules, was evaluated. The adhesiveness of FLS was determined by adhesion assay.


RESULTS
HVEM was detected in most cell types within rheumatoid synovial tissue, while only a few cells were positive for LIGHT. In RA patients, LIGHT expression was significantly up-regulated only in CD20+ B cells and monocytes, whereas the mean fluorescence intensity of HVEM was down-regulated in mononuclear cells. The stimulation of FLS with LIGHT resulted in the production of MMPs and the expression of adhesion molecules, which were efficiently inhibited by dexamethasone. LIGHT-mediated up-regulation of MMPs and intercellular adhesion molecule 1 was blocked by inhibitors of NF-kappaB and JNK, whereas up-regulation of vascular cell adhesion molecule 1 was blocked by inhibitors of phosphatidylinositol 3-kinase, as well as NF-kappaB.


CONCLUSIONS
These data suggest that binding of LIGHT with its receptors may play a role in the progression of inflammation within rheumatoid synovium, especially by mediating the interactions between infiltrating inflammatory cells and stromal cells. These findings thus emphasize the relevance of LIGHT as a potential therapeutic target in RA.
Kang
Young Mo
YM
Kyungpook National University School of Medicine, and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. ymkang@knu.ac.kr
Kim
So Young
SY
Kang
Jin Hee
JH
Han
Seung Woo
SW
Nam
Eon Jeong
EJ
Kyung
Hee Soo
HS
Park
Jae Yong
JY
Kim
In San
IS
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D010003:Osteoarthritis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000201:enzymology* / Q000473:pathology; D013585:Synovitis / Q000378:metabolism / Q000473:pathology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D045726:Metalloproteases