Role of TL1A in the pathogenesis of rheumatoid arthritis.
TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-alpha production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF-alpha or IL-1beta stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis.
Research Center, Entre Hospitalier de l'Université de Montréal, Notre-Dame Hospital, Montreal, Quebec, Canada.
Jun
J
Zhang
Xuehai
X
Wang
Hassan
H
Fahmi
Susan
S
Wojcik
James
J
Fikes
Youhua
Y
Yu
Jiangping
J
Wu
Hongyu
H
Luo
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000276:immunology / Q000378:metabolism; D024043:Collagen Type II / Q000494:pharmacology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000494:pharmacology; D007596:Joints / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology
D001323:Autoantibodies; D024043:Collagen Type II; D020381:Interleukin-17; D053583:Interleukin-1beta; D011994:Recombinant Proteins; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha