Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis.
OBJECTIVE
Lymphotoxin beta (LTbeta), a cytokine produced by T cells and B cells, plays a central role in the normal development of lymph nodes and is critical in the formation of ectopic germinal center reactions in rheumatoid synovitis. Because resident fibroblast-like synoviocytes (FLS) express receptors for LTbeta, we examined the consequences of FLS activation by LTbeta.


METHODS
FLS from patients with rheumatoid arthritis were isolated and examined for the expression of LTbeta receptor. FLS were incubated with LTalpha1beta2 and assayed for the production of cytokines and chemokines and the up-regulation of adhesion molecules.


RESULTS
Exposure of FLS to recombinant LTalpha1beta2 resulted in the production of multiple inflammatory cytokines and metalloproteinases, implicating FLS as amplifiers of the inflammatory process in the inflamed joint. Additionally, LTalpha1beta2 was found to up-regulate the expression of cell adhesion molecules, rendering FLS to efficient adhesion substrates for T cells. LTalpha1beta2 also induced production of the chemokines CCL2 and CCL5, which elicited transmigration activity of T cells. Upon stimulation with LTalpha1beta2, FLS did not acquire characteristics of follicular dendritic cells.


CONCLUSIONS
These data document that FLS are involved in multiple stages of the inflammatory process, including the recruitment and retention of lymphocytes in the synovial microenvironment. We propose that the heterotypic interaction between LTbeta-producing lymphocytes and responding FLS contributes to the establishment of complex lymphoid microstructures, and that this may be one element that defines susceptibility of the synovial membrane to lymphoid organogenesis.
Braun
Andrea
A
Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Takemura
Seisuke
S
Vallejo
Abbe N
AN
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism* / Q000494:pharmacology; D053308:Lymphotoxin-beta; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D014176:Protein Biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation
C111835:CCL2 protein, human; C483024:CCL5 protein, human; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D018836:Inflammation Mediators; C505886:LTB protein, human; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D011994:Recombinant Proteins; D020782:Matrix Metalloproteinases