A novel therapy of murine collagen-induced arthritis with soluble T1/ST2.
Rheumatoid arthritis is characterized by chronic inflammatory infiltration of the synovium, leading to eventual cartilage and bone destruction. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL-1R gene family, inhibits LPS-induced macrophage proinflammatory cytokine production. In this study, we report the therapeutic effect of sST2-Fc in the murine model of collagen-induced arthritis. A short term administration of sST2-Fc fusion protein significantly attenuated disease severity compared with controls treated with normal IgG. Histological examination revealed that while control IgG-treated mice developed severe cellular infiltration in the joints, synovial hyperplasia, and joint erosion, this pathology was profoundly reduced in sST2-Fc-treated animals. Treatment of sST2-Fc also down-regulated serum levels of IL-6, IL-12, and TNF-alpha. Spleen cells from the sST2-Fc-treated mice produced significantly less IFN-gamma, TNF-alpha, IL-6, and IL-12 compared with cells from the control mice when cultured with collagen in vitro. Finally, pretreatment with ST2-Fc markedly inhibited the ability of human monocytic THP1 cells to release TNF-alpha when cocultured with peripheral blood T cells from rheumatoid patients. Together these results demonstrate that sST2-Fc may provide a novel approach in treating chronic autoimmune conditions by inhibiting the release of proinflammatory cytokines.
Leung
Bernard P
BP
Division of Immunology, Infection, and Inflammation and Centre for Rheumatic Diseases, Royal Infirmary, University of Glasgow, Glasgow G11 6NT, Scotland, UK.
Xu
Damo
D
Culshaw
Shauna
S
McInnes
Iain B
IB
Liew
Foo Y
FY
D000818:Animals; D000917:Antibody Formation; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002450:Cell Communication; D024043:Collagen Type II / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000627:therapeutic use*; D051379:Mice; D008811:Mice, Inbred DBA; D011956:Receptors, Cell Surface / Q000502:physiology; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D024043:Collagen Type II; D016207:Cytokines; C486189:Il1rl1 protein, mouse; D007141:Immunoglobulin Fc Fragments; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha