Lymphotoxin beta-mediated stimulation of synoviocytes in RA

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Arthritis Rheum. 2004 Jul;50(7):2140-50.

Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid

arthritis.

Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM.

Mayo Clinic, Rochester, Minnesota.

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.

CONCLUSION: 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.

PMID: 15248211

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Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org