Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis.
OBJECTIVE
To evaluate the possible role of activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin (Lptn) in the pathogenesis of rheumatoid arthritis (RA).


METHODS
ATAC/Lptn levels in serum and synovial fluid samples were measured by sandwich enzyme-linked immunosorbent assay. Expression of messenger RNA for ATAC/Lptn in synovial tissues was analyzed by reverse transcription-polymerase chain reaction (PCR) and by in situ hybridization, and was quantitated by real-time PCR. The phenotype of peripheral blood mononuclear cells (PBMCs) expressing ATAC/Lptn was analyzed by intracellular cytokine staining and flow cytometry.


RESULTS
Levels of ATAC/Lptn were similar in sera and synovial fluids from RA patients (n = 20) and osteoarthritis controls (n = 15). In phorbol myristate acetate/ionomycin-stimulated PBMCs, ATAC/Lptn expression was detected in CD8+ T cells and in a significantly increased proportion of CD4+,CD28- T cells from RA patients as compared with healthy controls. In synovial tissues, ATAC/Lptn was predominantly localized in CD3+ T cells in the sublining layer. Lymphocytes, synovial macrophages, and, unexpectedly, fibroblast-like synoviocytes (FLS) were identified as major target cells for ATAC/Lptn in RA synovium, as determined by analysis of the ATAC/Lptn receptor XCR1. In vitro, ATAC/Lptn stimulation of FLS resulted in a marked down-regulation of matrix metalloproteinase 2 production.


CONCLUSIONS
These data indicate that in RA synovium, ATAC/Lptn is mainly produced by T cells. Considering its function as a lymphocyte-specific chemoattractant, ATAC/Lptn might be a key modulator for T cell trafficking in the pathogenesis of RA. In addition, functional studies suggest that ATAC/Lptn may exert additional immunomodulatory effects in RA.
Blaschke
Sabine
S
Department of Nephrology and Rheumatology, Georg-August-University, Robert-Koch Strasse 40, Göttingen 37075, Germany. sblasch@gwdg.de
Middel
Peter
P
Dorner
Brigitte G
BG
Blaschke
Volker
V
Hummel
Klaus M
KM
Kroczek
Richard A
RA
Reich
Kristian
K
Benoehr
Peter
P
Koziolek
Michael
M
Müller
Gerhard A
GA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D019744:Chemokines, C; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008222:Lymphokines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism
D019744:Chemokines, C; D008222:Lymphokines; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C092390:XCL1 protein, human; C018997:lymphotactin