The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis.
OBJECTIVE
The TNF superfamily member LIGHT has a T-cell co-stimulatory role and has previously been associated with inflammation and autoimmunity. To investigate its role in rheumatoid arthritis (RA), a disease where activated T cells contribute in a prominent way, we have analysed the expression of LIGHT and its receptors in RA and analysed its effects on synovial fibroblasts in vitro.


METHODS
The expression of LIGHT was measured in synovial tissues and fluids and the receptors of LIGHT were detected on synovial fibroblasts derived from patients with RA and osteoarthritis (OA). The effects of recombinant LIGHT on the production of proinflammatory cytokines and proteases and on the apoptosis of synovial fibroblasts was assessed.


RESULTS
LIGHT mRNA was present in synovial tissues of patients with RA but not with OA. Correspondingly, soluble LIGHT protein could be detected in RA synovial fluid samples at much higher levels than in synovial fluid from patients with OA. Immunohistochemical detection of LIGHT and analysis of synovial fluid cells by flow cytometry revealed CD4 T cells as the major source of LIGHT in the rheumatoid joint. Synovial fibroblasts from RA patients were found to express the LIGHT receptors HVEM and LTbetaR. Recombinant LIGHT induced RA synovial fibroblasts to upregulate MMP-9 mRNA, CD54 and IL-6 in an NF-kappaB-dependent fashion. In vitro, exposure of cultured synovial fibroblasts to LIGHT reduced FAS-mediated apoptosis significantly, without affecting the rate of spontaneous apoptosis.


CONCLUSIONS
The results provide evidence for a novel T-cell-dependent activation of synovial fibroblasts by LIGHT in joints of patients with RA, contributing to an inflammatory and destructive phenotype.
Pierer
M
M
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Gloriastrasse 25, 8091 Zurich, Switzerland.
Brentano
F
F
Rethage
J
J
Wagner
U
U
Hantzschel
H
H
Gay
R E
RE
Gay
S
S
Kyburz
D
D
D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D007975:Leukotriene B4 / Q000032:analysis / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013582:Synovial Fluid / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011994:Recombinant Proteins; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D018799:Intercellular Adhesion Molecule-1; D007975:Leukotriene B4; D020780:Matrix Metalloproteinase 9